Compositions and Methods for the Treatment of Presbyopia

ABSTRACT

The invention provides compositions and methods for the treatment of presbyopia. In a preferred embodiment correction of presbyopia occurs without reduction in distance vision acuity. The compositions of the invention preferably contain a muscarinic agonist and a cycloplegic agent.

BACKGROUND OF THE INVENTION

As a person ages the minimum distance from the eye at which an objectwill come into focus, provided distance vision is corrected or isexcellent unaided, increases. For example, a 10 year-old can focus on anobject or a “focal point” only three inches (0.072 meters) from theireye while still retaining excellent distance vision; a 40 year-old atsix inches (0.15 meters); and a 60 year-old at an inconvenient 39 inches(1.0 meter). This condition of increasing minimum focal length inindividuals with excellent unaided distance vision is called presbyopia,loosely translated as “old-man eye”.

Excellent unaided distance vision is also known as emmetropia. Theinability to focus on distant focal points is known as myopia and theinability to focus on near focal points is known as hyperopia.Specifically, “distance” vision is considered any focal point 1 meter ormore from the eye and near vision is any focal point less than 1 meterfrom the eye. The minimum focal length at which an object will come intofocus is known as the “near point”. The change in focus from distance tothe near point and any focal point in between is called accommodation.Accommodation is often measured in diopters. Diopters are calculated bytaking the reciprocal of the focal length (in meters). For example, thedecrease in accommodation from a 10 year-old eye to a 60 year-old eye isabout 13 diopters (1±0.072 meters=13.89 diopters; 1±1 meter=1 diopter).

The highest incidence of first complaint of presbyopia occurs in peopleages 42-44. Presbyopia occurs because as a person ages the eye'saccommodative ability which uses near reflex-pupil constriction,convergence of the eyes and particularly ciliary muscle contractiondecreases. This reduction in accommodation results in an inadequatechange in the normal thickening and increased curvature of the anteriorsurface of the lens that is necessary for the shift in focus fromdistant objects to near objects. Important near focus tasks affected bypresbyopia include viewing computer screens (21 inches) and readingprint (16 inches).

Presbyopia is a normal and inevitable effect of ageing and is the firstunmistakable sign for many in their forties that they are getting older.One study found that more than 1 billion people worldwide werepresbyopic in 2005. This same study predicted that number to almostdouble by the year 2050. If everyone over the age of 45 is considered tobe presbyopic, then an estimated 122 million people in the United Statesalone had presbyopia in 2010. As baby boomers reach the critical age,this number is only going to increase.

Presbyopia carries with it a stigma resulting from the limitation inability to quickly function at many tasks requiring focusing at bothdistant and near points, which once occurred almost immediately. In thepresbyopic patient, these tasks can be performed only by the use ofeyeglasses, contact lenses or after undergoing invasive surgery. Onesuch optical modification, the monovision procedure, can be executedwith the use of glasses, contact lenses or even surgery. The monovisionprocedure corrects one eye for near focus and the other eye for distancefocus. However, monovision correction is normally accompanied by loss ofdepth perception and distance vision particularly in dim light (e.g.night). Other surgical procedures that have been developed to relievepresbyopia include: (1) the implantation of intraocular lenses(INTRACOR®; registered trademark of Technolas Perfect Vision GMBH); (2)reshaping of the cornea (PresbyLASIK and conductive keratoplasty); (3)scleral band expansion; and (4) implantation of corneal inlays (FlexivueMicrolens®; registered trademark of PresbiBio LLC, Kamra®; registeredtrademark of AcuFocus, Inc. and Vue+). Kamra® corneal inlaysmanufactured by AcuFocus work by inlaying a pinhole on the cornea toincrease the depth of focus. A similar effect can be achieved withgeneral miotic agents, such as pilocarpine (a non-selective muscarinicacetylcholine receptor agonist), carbachol (a non-selective muscarinicacetylcholine receptor agonist), and phospholine iodide (anacetylcholinesterase inhibitor). These general miotic agents triggerincreased ciliary muscle contraction and induce accommodation of anyremaining reserves, improving near vision at the expense of distancevision in individuals who still retain some accommodative function.While these general miotic agents also create improved depth of focusvia a pinhole effect induced by pupillary miosis (i.e. constriction), tothe degree accommodation occurs, the pinhole effect only partiallyoffsets the induced accommodative myopia for distance. In some cases,such as with pilocarpine or carbachol, the induced accommodation maycreate up to 5 diopters or more of induced myopia resulting in inducedmyopia causing blurred distance vision generally and during shift of thefocal point from distance to near. These general miotic agents alsocause substantial redness, severe nasal congestion and create ciliarymuscle spasms, which commonly induces discomfort that can be severe andlong-lasting. In extreme cases, such ciliary muscle spasms can result inretinal detachment.

The holy grail of topical induced presbyopic correction results in noreduction in distance vision. Currently all miotic agents (e.g.muscarinic agonists) cause a reduction in distance vision by convertingpoints of distance focus to a near point. Miotic agents enhance nearvision in this manner through contraction of the ciliary muscle,particularly the circumferential radial component, however this samecontraction thereby causes reduction in distance vision. Distance visionis reduced by as much as 5 to 11 diopters (e.g. pilocarpine 2%-4%) insome cases, particularly for those with some residual near focus(accommodation). While this can be modulated by reducing theconcentration of the miotic agent, the degree of ciliary inducedaccommodation is thereby also reduced limiting the closeness of the nearpoint of focus. Further, any advantage of increased depth of focus frompinhole optics that might enhance both distance and near vision requiressufficiently great pupil constriction. This pupil constriction requireshigher concentrations of muscarinic agonists than the distance blurresulting from even modest concentrations will allow.

Miotic agents have been described in various patent and patentapplications for the treatment of presbyopia. U.S. Pat. Nos. 6,291,466and 6,410,544 describe the use of pilocarpine to regulate thecontraction of ciliary muscles to restore the eye to its resting stateand potentially restore its accommodative abilities.

US Patent Application Publication No. 2010/0016395 describes the use ofpilocarpine with the non-steroidal anti-inflammatory, diclofenac, toreduce brow ache from ciliary spasm, but does not prevent induced miosisand distance blur. International PCT Application PublicationWO/2013/041967 describes the use of pilocarpine with oxymetazoline ormeloxicam to temporarily overcome ocular conditions such as presbyopiaand possibly slightly decreases the degree of ciliary muscle contractiondue to reduced pilocarpine levels in the ciliary body due tovasoconstriction of the ciliary vasculature. Specifically, ciliaryinduced miosis results in about 0.7 lines of distance vision loss,equating to an eye that is reduced to 20.27 distance vision. Thisreduction is about a 26% drop in distance acuity from the otherwise20.20 best corrected vision.

U.S. Pat. No. 8,299,079 (HEK Development LLC) describes the use ofdirect acting general miotic agents such as pilocarpine, carbachol andphospholine iodide with brimonidine at a concentration from 0.05% to3.0% w/v. However, the use of brimonidine concentrations at or above0.05% w/v results in increased dryness and with regular use possiblerebound hyperemia. For example, rebound redness occurs in 25% ofpatients using brimonidine 0.20% w/v (Alphagan®, registered trademark ofAllergan, Inc.) twice daily. Further brimonidine only slightly reducesdilation of the pupil in scotopic conditions, does not enhance itsconstriction or affect ciliary induced myopia.

US Patent Application No. 2014/0113946 (Allergan) discloses means oftreating presbyopia using pilocarpine and an alpha agonist, such asoxymetazoline. Examples using pilocarpine 1.0% disclose a loss of 0.7lines of average distance vision (26% reduction) and demonstrate pupilconstriction greater than 2.0 millimeters (“mm”) at all time points,ranging from 2.1 to 3.2 over a six hour period. Oxymetazolineconcentrations in preferred embodiments of 0.05% and 0.125% are both ator above concentrations known to be associated with rebound hyperemia(0.05%) and labeled for maximum daily use of three days (Visine L.R.®;Visine L.R. is a registered trademark of Johnson & Johnson Corp.).

These attempts at miotic treatment for presbyopia all induce transientmyopia of reducing distance vision by 20% or worse for many subjects,caused by ciliary contraction. These attempts also often inducebothersome and not infrequently painful ciliary brow ache analogous to amoderately severe migraine. In some cases, miotic treatments induceimproved near vision that begins deteriorating within a few hours (i.e.US 2014/0113946 loss of effect starting at about 4 hours and degradingrapidly).

Current efforts to achieve presbyopic treatment with miotic agents arelimited by the accommodative distance blur and ciliary induced brow achethat severely limit usefulness. Specifically, due to the need for lowerconcentrations that may somewhat reduce but not eliminate thesebothersome side effects, only limited pupillary miosis occurs. Thislimited pupillary miosis limits depth of focus pinhole optic benefit tonear vision and distance vision. Both distance and near optimal visionpotential is compromised. Additionally, this limited pupillary miosis issufficient only to partially offset the distance blur resulting fromgreater near point of focus. Further, only a few hours duration of thislimited action can be achieved. Thus, there is a need in the art for atreatment of presbyopia that is non-invasive and convenient with minimalside effects. Specifically, there is a need for an ophthalmologicalcomposition that will allow a person suffering from presbyopia to focuson near objects without significant side effects such as diminisheddistance vision, blurred vision, pain, and redness, impaired nightdriving or incapacitating dim light vision, induced nasal congestion, orrisk of retinal detachment.

SUMMARY OF THE INVENTION

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist, wherein the muscarinic agonist preferentiallyactivates M1 and M3 muscarinic acetylcholine receptors. In still morepreferred embodiments the muscarinic agonist is more highly selectivefor M1 than M3. In certain embodiments, the present invention isdirected to compositions and methods for the treatment of presbyopiacomprising a muscarinic agonist that preferentially activates M1 and M3muscarinic acetylcholine receptors.

In certain embodiments, the present invention is directed tocompositions and methods for the treatment of presbyopia comprising amuscarinic agonist that activates only M1 muscarinic acetylcholinereceptors.

In certain embodiments, the present invention is directed tocompositions for the treatment of presbyopia comprising a muscarinicagonist, preferably selected from the group consisting of pilocarpine,aceclidine, talsaclidine, sabcomeline, cevimeline, WAY-132983, AFB267B(NGX267), AC-42, AC-260584, 77-LH-28-1, and LY593039 or anypharmaceutically acceptable salts, esters, analogues, prodrugs orderivatives thereof and a cycloplegic agent, preferably selected frompirenzepine, tropicamide, cyclopentolate hydrochloride,4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), AF-DX 384,methoctramine, tripitramine, darifenacin, solifenacin, tolterodine,oxybutynin, ipratropium, oxitropium, tiotropium, otenzepad and acombination thereof.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising amuscarinic agonist and a cycloplegic agent in a ratio greater than about25:1, preferably greater than about 40:1.

In certain embodiments, the present invention is directed toophthalmological compositions for the treatment of presbyopia comprisingpilocarpine or any pharmaceutically acceptable salts, esters, analogues,prodrugs or derivatives thereof and a cycloplegic agent, preferablyselected from pirenzepine, tropicamide, cyclopentolate hydrochloride,4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), AF-DX 384,methoctramine, tripitramine, darifenacin, solifenacin, tolterodine,oxybutynin, ipratropium, oxitropium, tiotropium, otenzepad and acombination thereof.

In certain embodiments, the present invention is directed toophthalmological compositions for the treatment of presbyopia comprisingpilocarpine at a concentration from about 0.5% to about 2.5% w/v,preferably about 1.5% w/v and a cycloplegic agent at a concentrationfrom about 0.010% to about 0.1% w/v.

In certain embodiments, the present invention is directed toophthalmological compositions for the treatment of presbyopia comprisingpilocarpine or any pharmaceutically acceptable salts, esters, analogues,prodrugs or derivatives thereof and tropicamide.

In certain embodiments, the present invention is directed toophthalmological compositions for the treatment of presbyopia comprisingpilocarpine at a concentration from about 0.5% to about 2.5% w/v,preferably about 1.5% w/v and 0.95% w/v and tropicamide at aconcentration from about 0.010% to about 0.1% w/v, preferably about0.035% w/v and about 0.015% w/v.

The present invention is further directed to a method for treatingpresbyopia comprising administering to a patient in need thereof apharmaceutically effective amount of a composition of the presentinvention.

The present invention is further directed to a method for treatingpresbyopia without reducing distance vision acuity comprisingadministering to a patient in need thereof a pharmaceutically effectiveamount of a composition of the present invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphical representation of the effects of pilocarpine andaceclidine with or without tropicamide and with or without a carrier onnear and distance vision in a patient over the age of 45.

FIG. 2 is a graphical representation of the effects of myopic sphericalequivalent fraction on distance vision acuity at various pupil sizes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compositions and methods oftreating presbyopia, irregular astigmatism, and/or refractive error,comprising administering to a patient in need thereof a pharmaceuticalcomposition comprising a muscarinic agonist that preferentiallyactivates M1 and M3 muscarinic acetylcholine receptors, preferablyactivate M1 more than M3 and most preferably aceclidine or itsderivatives. Pilocarpine and aceclidine have been surprisingly andunexpectedly discovered to provide enhanced presbyopic reversal withnegligible side effects day or night (when viewing includes one or moredirect or reflected light sources) using compositions of the presentinvention.

Aceclidine is traditionally used as a treatment for glaucoma. Whenaceclidine is used to treat glaucoma it is normally stored in atwo-bottle system; one bottle containing the lyophilized aceclidine andthe second bottle containing the diluent necessary to reconstitute thelyophilized aceclidine before topical instillation. Romano J. H.,Double-blind cross-over comparison of aceclidine and pilocarpine inopen-angle glaucoma, Brit J Ophthal, August 1970, 54(8), 510-521. It isa further aspect of the present invention to provide an aqueousaceclidine composition that is stable in combination with cold chainstorage. It is yet a further aspect of the present invention to providea method of stabilizing aqueous aceclidine by combining effectiveexcipients, pH ranges and temperature ranges.

The compositions and methods of the present invention treat presbyopiaby improving depth of focus in patients with presbyopia by administeringan ophthalmological composition to the eye that:

-   -   1) reduces pupil dilation in the dark or in dim light;    -   2) produces a particular degree and duration of miosis without        sufficient accommodation to overcome pinhole optic distance        vision enhancement;    -   3) enhances near vision with depth of focus near enhancement        further improved by residual sub distance threshold pinhole        optic degradation still sufficient to provide additive near        benefit; and    -   4) provides cosmetic whitening and/or induce redness        prophylaxis. The compositions and methods of the present        invention also do not cause significant pupil rebound,        tachyphylaxis, ciliary spasms, induction of myopia or reduction        in distance vision. Additionally, the compositions and methods        of the present invention allow for the further improvement in        visual acuity and depth perception of binocular (both eyes)        treatment.

The ophthalmological composition of the present invention surprisinglycreates a pupil of from about 1.5 to about 2.4 mm at the anterior irisplane and about 2.0 mm at the corneal surface with negligible increasein accommodative tone and with a reduction or ablation of the rednessthat is otherwise a hallmark of the use of miotic agents. This pupilmiosis with greatly diminished or absent accommodative tone is superiorto the pinhole effect of the Kamra® and Flexivue Microlens® cornealinlays. Pupil miosis is superior because the constriction of the actualpupil does not result in the attendant severe night vision disturbancecaused by the light scattering borders of the pre-corneal pinholescreated by the inlays. Further pupil miosis provides a greater field ofvision and transmission of more focused light. The use of aceclidine hasa minimal effect on the longitudinal ciliary muscle, thus reducing riskof retinal detachment when compared to the use of general muscarinicagonists such as carbachol. The further inclusion of a cycloplegic agentresulted in only 0.04 mm of anterior chamber shallowing. Aceclidineparticularly as enhanced for the present invention also has greatermagnitude, duration, and control of minimum pupil diameter. Compositionsof the present invention achieve these advantages while havingnegligible effects on accommodation, thus avoiding the distance blurtypically seen in patients as a response to pilocarpine and/or carbacholinduced miosis. Any effects on accommodation may be further reduced ortotally eliminated in preferred embodiments with a cycloplegic agent.Aceclidine is capable of producing the increased depth of focus by pupilmiosis described in the present invention without the need of aselective α-2 adrenergic receptor agonist (“α-2 agonist”). Particularlyenhanced miosis occurs with use of compositions of the presentinvention, thus making it possible to use an α-2 agonist at lowconcentrations to reduce eye redness. Further, due to the apparent andsurprisingly selective nature of aceclidine, administration to the eyealmost exclusively affects pupil miosis rather than ciliary musclecontraction. Thus, the administration of aceclidine results in pupilmiosis without accommodation and attendant distance blur. However,aceclidine may cause some redness and brow ache, and without formulationenhancement of the present invention may produce less than optimal pupilmiosis or at extremely high concentration more than desired peak miosiswith added dimming of vision in dim or absent lighting.

Certain embodiments of the present invention enhance the discoveredpreferred degree of pupillary miosis by providing a consistent range ofeffect of about 1.50-2.20 mm for most patients using a preferredembodiment of a nonionic surfactant and viscosity enhancer. Similarbenefit may be achieved using other permeation enhancers, particularlyCarbopol® (polyacrylic acid or carbomer), and various viscosityadditives that increase drug residence time, such as xanthan gums, guargum, alginate, and other in situ gels well known to experts in the art.The present invention further prevents nasal congestion otherwiseoccurring when substantial aceclidine levels reach the nasal mucosa, dueto the rheologic properties of the preferred embodiment.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine.

In certain other embodiments the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine and a cycloplegic agent.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine and a selective α-2 adrenergic receptor agonist.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisingaceclidine, a cycloplegic agent and a selective α-2 adrenergic receptoragonist.

In certain other embodiments, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprisinga general miotic agent and a cycloplegic agent.

In certain other embodiments, the present invention is directed to anophthalmological composition of the present invention comprising:

a general miotic agent, a muscarinic agonist or aceclidine;

-   -   optionally a cycloplegic agent;    -   optionally a selective α-2 adrenergic receptor agonist;    -   a viscosity enhancer; and    -   a surfactant selected from the group consisting of an anionic        surfactant, a nonionic surfactant, and a combination thereof.

In one embodiment, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;a cycloplegic agent at a concentration from about 0.010% to about 0.1%w/v, preferably selected from pirenzepine, tropicamide, cyclopentolatehydrochloride, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP),AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin,tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium, otenzepadand a combination thereof and more preferably tropicamide;a surfactant, preferably selected from polyoxyl 40 stearate, a gammacyclodextrin, sulfobutylether β-cyclodextrin, 2-hydroxypropylcyclodextrin, sodium lauryl sulfate, sodium ester lauryl sulfate, apoloxamer, a polysorbate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monostearate, sorbitan monooleate, a polyoxyl alkyl, acyclodextrin and combinations thereof and more preferably polyoxyl 40stearate;a tonicity adjustor, preferably selected from mannitol, sodium chloride,potassium chloride, glycerin and combinations thereof and morepreferably mannitol; andoptionally a viscosity enhancer, preferably the viscosity enhancer isnot a polysaccharide.

In another embodiment, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;a cycloplegic agent at a concentration from about 0.010% to about 0.1%w/v;a surfactant;a tonicity adjustor; andone or more excipients selected from a viscosity enhancer selected fromthe group consisting of guar gum, hydroxypropyl-guar, xanthan gum,alginate, chitosan, Gelrite®, hyauluronic acid, dextran, and a carbomer,preferably carbomer 934 or carbomer 940 wherein the viscosity is fromabout 1 to about 5,000 centipoise (“cps”) prior to topical installationand from about 1 to about 50 cps upon topical installation, preferablyfrom about 1 to about 5,000 cps at from about 2 to about 8° C. and anantioxidant selected from citrate, citric acid monohydrateethylenediaminetetraacetic acid, disodium ethylenediaminetetraaceticacid, dicalcium diethylenetriamine pentaacetic acid and combinationsthereof, preferably citric acid monohydrate.

In a preferred embodiment, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;tropicamide at a concentration from about 0.010% to about 0.1% w/v;polyoxyl 40 stearate at a concentration from about 2.0% to about 10.0%w/v;mannitol at a concentration from about 0.5% to about 6.0% w/v;a buffer selected from acetate buffer, citrate buffer, phosphate bufferand citrophosphate buffer at a concentration of about 3 millimolar;optionally citric acid monohydrate at a concentration from about 0.1% toabout 0.2% w/v;optionally a viscosity enhancer selected from carbomer 934 and carbomer940 at a concentration from about 0.01% to about 1.0% w/v; andoptionally benzalkonium chloride (“BAK”) at a concentration of about0.02% w/v or a combination of BAK, sorbate and borate,wherein the pH of the composition is from about 4.75 to about 5.0 andwherein the viscosity of the composition is from about 1 to about 50 cpsupon topical installation.

In another preferred embodiment, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;tropicamide at a concentration from about 0.010% to about 0.1% w/v;polyoxyl 40 stearate at a concentration of about 4.0% w/v;mannitol at a concentration from about 0.5% to about 6.0% w/v;citric acid monohydrate at a concentration from about 0.1% to about 0.2%w/v;carbomer 934 at a concentration from about 0.01% to about 1.0% w/v, anda buffer selected from acetate buffer, citrate buffer, phosphate bufferand citrophosphate buffer at a concentration of about 3 millimolar,wherein the pH of the composition is about 4.75 and wherein theviscosity of the composition is from about 1 to about 5,000 cps at fromabout 2 to about 8° C.

In another preferred embodiment, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;tropicamide at a concentration from about 0.010% to about 0.1% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;mannitol at a concentration of about 4.0% w/v; anda buffer selected from acetate buffer, citrate buffer, phosphate bufferand citrophosphate buffer at a concentration of about 3 millimolar,wherein the pH of the composition is about 5.0.

In another preferred embodiment, the present invention is directed to anophthalmological composition for the treatment of presbyopia comprising:

aceclidine at a concentration from about 0.25% to about 2.0% w/v;tropicamide at a concentration from about 0.010% to about 0.1% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;mannitol at a concentration of about 0.5% to about 6% w/v;citric acid monohydrate at a concentration from about 0.1% to about 0.2%w/v;carbomer 940 at a concentration from about 0.01% to about 1.0% w/v, anda buffer selected from acetate buffer, citrate buffer, phosphate bufferand citrophosphate buffer at a concentration of about 3 millimolar,wherein the pH of the composition is from about 4.75 to about 5.0 andthe viscosity of the composition is from about 1 to about 5,000 cps atfrom about 2 to about 8° C. In some preferred embodiments of the aboveformulations the aceclidine concentration is about 1.35% to about 1.75%w/v, the mannitol concentration is about 1.0% to 2.5% w/v, and thecarbomer 940 concentration is about 0.09% to 1.0% w/v (or equivalentviscosity using any other nonpolysaccharide viscosity agent such ascarbomer 934).

The present invention is further directed to a method of treating arefractive error of the eye in a subject in need thereof comprisingadministering to a subject in need thereof a pharmaceutically acceptableamount of a composition of the present invention wherein the refractiveerror of the eye is selected from presbyopia, myopia, hyperopia,astigmatism or a combination thereof.

The present invention is further directed to a method for treatingpresbyopia comprising administering to a patient in need thereof acomposition of the present invention.

The present invention is further directed to a method for treatingpresbyopia without inducing ciliary brow ache comprising administeringto a patient in need thereof a pharmaceutically effective amount of acomposition of the present invention.

The present invention is further directed to a method for enhancing nearvision and distance vision without inducing ciliary brow ache comprisingadministering to a patient in need thereof a pharmaceutically effectiveamount of a composition of the present invention.

The present invention is further directed to a method for treatingpresbyopia via enhancing pinhole optics depth of focus comprisingadministering to a patient in need thereof a pharmaceutically effectiveamount of a composition of the present invention.

The present invention is further directed to a method for treating oftreating presbyopia via enhancing pinhole optics distance depth of focusand pinhole optics near depth of focus comprising administering to apatient in need thereof a pharmaceutically effective amount of acomposition of the present invention, wherein slight ciliary inducedmyopia occurs without reduction in distance vision.

The present invention is further directed to a method for inducingpupillary miosis focus comprising administering to a patient in needthereof a pharmaceutically effective amount of a composition of thepresent invention, wherein a substantial reduction in ciliarycontraction occurs, an improvement in pinhole optics near depth of focusoccurs, near vision and distance vision is improved and ciliary inducedbrow ache does not occur.

The present invention is further directed to a method for enhancingpinhole optics depth of focus and near vision depth of focus comprisingadministering to a patient in need thereof a pharmaceutically effectiveamount of a composition of the present invention, wherein ciliary musclecontraction induced miosis is reduced to a degree that does not reducedistance pinhole optics and wherein, optionally, slight additiveaccommodation occurs.

The present invention is further directed to a method for treating arefractive error of the eye comprising administering to a patient inneed thereof a pharmaceutically acceptable amount of a composition ofthe present invention, wherein the size of the pupil is reduced to fromabout 1.5 to about 2.5 millimeters, preferably from about 1.7 to about2.0 millimeters and wherein the refractive error is selected from thegroup consisting of corneal irregular astigmatism, an ectasia inducedcorneal irregularity, a pellucid induced corneal irregularity, a higherorder aberration and a refractive surgery induced higher orderaberration.

The present invention is further directed to a method of increasing thevisual depth of field (i.e. depth of focus) comprising administering toa subject in need thereof a pharmaceutically effective amount of anophthalmological composition of the present invention.

The present invention is further directed to a method of increasing thevisual depth perception upon improving near vision unaided comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of an ophthalmological composition of the present invention inboth eyes (binocular vision), wherein such binocularity further enhancesnear vision beyond that of either eye separately.

The present invention is further directed to a method of improvingvision in a subject with ammetropia (vision abnormality), comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of a composition of the present invention.

The present invention is further directed to a method of improvingvision in a subject with ammetropia, comprising administering to asubject in need thereof a pharmaceutically effective amount of acomposition of the present invention, wherein ammetropia is selectedfrom the group consisting of nearsightedness, farsightedness, regularastigmatism, irregular astigmatism and high degrees of regularastigmatism.

The present invention is further directed at eliminating opticalaberrations induced by corneal irregularity, opacities, or very highdegrees of regular astigmatism that include regions adjacent orperipheral to the central 1.5 mm optical zone, and thereby inducingimproved visual acuity and quality of vision by filtering out theseaberrant optics in those suffering from irregular astigmatism or highdegrees of more regular astigmatism, such as occurs in conditions suchas keratoconus, photorefractive keratectomy induced corneal haze,diffuse lamellar keratitis (“DLK”) (post-lasik DLK), other iatrogeniccorneal induced irregularity such as cataract incision, glaucomafiltering blebs, implanted glaucoma valves, corneal inlays with orwithout removal, ectasia post corneal surgery (lasik), and secondary toinfection.

The present invention is further directed at improving acuity relativeto existing uncorrected refractive error. Upon this improved acuity,patients now requiring toric contact lenses for astigmatism with reducedcomfort and optics that may shift during each blink may in many casesrequire only non-toric soft contact lenses or no contact lenses.Further, those requiring gas permeable contact lenses may no longerrequire contact lenses or only require much more comfortable softcontact lenses. Patients with high degrees of astigmatism may nowrequire no correction or reduced astigmatic correction. Patients withsmall to moderate degrees of nearsightedness may require less correctionor no longer require correction. Patients with small to moderate degreesof hyperopia (farsightedness) may require no correction or reducedcorrection.

The present invention is directed to methods and ophthalmologicalcompositions for improving eye sight. In a preferred embodiment thepresent invention is directed to methods and ophthalmologicalcompositions for the treatment of presbyopia. In a more preferredembodiment the present invention is directed to ophthalmologicalcompositions comprising aceclidine. In a yet more preferred embodimentpresent invention is directed to ophthalmological compositionscomprising aceclidine and a low-dose cycloplegic agent. In a mostpreferred embodiment the present invention is directed toophthalmological compositions comprising aceclidine, a low-dosecycloplegic agent and a combination of inactive ingredients that makeeffective and/or enhance aceclidine.

The present invention is further directed to a method for stabilizingthe composition of claim 1 comprising maintaining the composition at atemperature from about 2 to about 8° C.

The present invention is further directed to a method for stabilizing anaqueous aceclidine composition comprising the steps of:

-   -   adding a surfactant selected from polyoxyl 40 stearate, a gamma        cyclodextrin, sulfobutylether β-cyclodextrin, 2-hydroxypropyl        cyclodextrin, sodium lauryl sulfate, sodium ester lauryl        sulfate, a poloxamer, a polysorbate, sorbitan monolaurate,        sorbitan monopalmitate, sorbitan monostearate, sorbitan        monooleate, a polyoxyl alkyl, a cyclodextrin and combinations        thereof to the composition, preferably polyoxyl 40 stearate;    -   adding a tonicity adjustor selected from mannitol, sodium        chloride, potassium chloride, glycerin and combinations thereof,        preferably mannitol;    -   optionally adding a viscosity enhancer selected from the group        consisting of guar gum, hydroxypropyl-guar, xanthan gum,        alginate, chitosan, Gelrite®, hyauluronic acid, dextran, a        carbomer and combinations thereof to the composition, preferably        carbomer 940,    -   buffering the pH of the composition to from about 4.0 to about        6.0, preferably 4.75; and    -   maintaining the composition at a temperature from about 2 to        about 8° C.

The present invention is further directed to a method for stabilizing anaqueous aceclidine composition comprising the steps of:

-   -   adding polyoxyl 40 stearate,    -   adding mannitol;    -   adding carbomer 940,    -   buffering the pH of the composition to 4.75; and    -   maintaining the composition at a temperature from about 2 to        about 8° C.

The combination of aceclidine and a low concentration of a selective α-2adrenergic receptor agonist (α-2 agonist or α-2 adrenergic agonist),such as fadolmidine, brimonidine or guanfacine, allows for the desiredmiotic effect with diminished or no redness. The use of lowconcentrations of a selective α-2 agonist results in substantialreduction of hyperemia with greatly reduced risk of rebound hyperemiathat is found in concentrations of about 0.06% w/v or more. Furthermore,the use of low concentrations of selective α-2 agonist does notadversely modify the pupil constriction caused by aceclidine. Incontrast, the use of brimonidine 0.20% w/v, when topically applied forpupil modulation for night vision, result in tachyphylaxis of pupilmodulation due to α-2 receptor upregulation in almost 100% of treatedsubjects within four weeks of use.

Unexpectedly, the addition of a cycloplegic agent results in reductionof any brow ache or associated discomfort by further reducing the degreeof ciliary spasms on topical instillation without impairing the mioticresponse. This lack of impairment of the miotic response is anunexpected surprising discovery, as particular cycloplegic agents, suchas tropicamide, have known pupil dilating effects at concentrations aslow as 0.01% w/v (Grünberger J. et al., The pupillary response test as amethod to differentiate various types of dementia, Neuropsychiatr, 2009,23(1), pg 57). More specifically cycloplegic agents cause pupilmydriasis (i.e. dilation of the radial muscle of the iris). Further, theaddition of a cycloplegic agent to the miotic agent unexpectedlyincreases the time at which the pupil maintains the desired size rangewithout becoming too restricted. Peak miotic effect at 30-60 minutes canbe titrated in inverse relation to the cycloplegic concentration. Theconcentrations of tropicamide discovered in the present inventionapparently cause more relaxation of the ciliary muscle than the irisradial musculature. In fact, iris mydriasis is discovered to besuppressed by the addition of tropicamide to compositions containingconcentrations of aceclidine used in the present invention, with insteada more consistent level of miosis for the duration of the miotic effect.Additionally and quite surprisingly, unexpectedly, and beneficially theaddition of tropicamide can reduce the degree of peak pupil miosiswithout inducing mydriasis thereby creating a more constant and idealpupil size throughout the drug induced miosis. This more consistentpupil size allows for beneficial near and distance vision without theadverse dimming or loss of resolution due to diffraction limits at thevery reduced pupil sizes seen at peak pupil miosis (e.g. 1.25 mm).

General miotic agents, such as pilocarpine, carbachol and phospholinediesterase, are capable of causing pupil miosis resulting in improvednear vision of presbyopic patients. However, there is an inversereduction in distance vision associated with these general miotic agentsfrom miosis at peak effect and accommodation that is to a lesser extentalso seen with aceclidine. The co-administration of a cycloplegic agentwith aceclidine surprisingly results in a complete attenuation of thisreduction in distance vision. Additionally, adding a cycloplegic agentto pilocarpine has surprisingly been found to even reduce the greaterdistance blur normally associated with pilocarpine.

Comfort, safety, and efficacy of a preferred embodiment of anophthalmological composition of the present invention results from thepresence of a nonionic surfactant, such as cyclodextrin alpha, beta, orgamma chains, preferably 2-hydroxypropyl beta-cyclodextrin (“HPβCD”),and or sulfobutyl ether derivative of β-cyclodextrin (Captisol®),polyoxyl 40 stearate or poloxamer 407; a viscosity enhancing agent, suchas carboxymethyl cellulose (“CMC”); a tonicity adjustor, such as sodiumchloride; a preservative, such as benzalkonium chloride and a pH fromabout 5.0 to about 8.0. Further, an increase in the concentration of theviscosity agent and the electrolyte may result in reduced redness.Specifically, increasing CMC from 0.50% to 0.75% w/v (preferably 0.80%w/v) and sodium chloride from 0.25% to 0.50% w/v results in reducedredness.

The viscosity of compositions of the present invention comprising aviscosity enhancer may be from about 1 to about 5,000 cps prior totopical instillation in the eye. As a result of the shear force appliedto the composition as it exits the device used for administration theviscosity is lowered to a range from about 1 to about 50 cps upontopical instillation, preferably from about 15 to about 35 cps.

DEFINITIONS

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, from acombination of the specified ingredients in the specified amounts.

The term “stabilizing”, as used herein, refers to any process whichfacilitates and/or enables an active agent to remain in solution. Theterm “stabilizing”, as used herein, also refers to any means or processwhich inhibits and/or reduces the tendency of a muscarinic agonist,including aceclidine or pilocarpine, to degrade.

As used herein, all numerical values relating to amounts, weights, andthe like, that are defined as “about” each particular value is plus orminus 10%. For example, the phrase “about 5% w/v” is to be understood as“4.5% to 5.5% w/v.” Therefore, amounts within 10% of the claimed valueare encompassed by the scope of the claims.

As used herein “% w/v” refers to the percent weight of the totalcomposition.

As used herein the term “subject” refers but is not limited to a personor other animal.

The term muscarinic receptor agonist (“muscarinic agonist”) encompassesagonists that activate muscarinic acetylcholine receptors (“muscarinicreceptors”). Muscarinic receptors are divided into five subtypes namedM1-M5. Muscarinic agonists of the present invention include thosemuscarinic agonists that preferentially activate M1 and M3 receptorsover M2, M4 and M5 receptors (“M1/M3 agonists”). M1/M3 agonists includebut are not limited to pilocarpine, aceclidine, xanomeline,talsaclidine, sabcomeline, cevimeline, alvameline, arecoline,milameline, SDZ-210-086, YM-796, RS-86, CDD-0102A(5-[3-ethyl-1,2,4-oxasdiazol-5-yl]-1,4,5,6-tetrahydropyrimidinehydrocholoride), N-arylurea-substituted 3-morpholine arecolines,VUO255-035(N-[3-oxo-3-[4-(4-pyridinyl)-1-piperazinyl]propyl]-2,1,3-benzothiadiazole-4-sulfonamide),benzylquinolone carboxylic acid (BQCA), WAY-132983, AFB267B (NGX267),AC-42, AC-260584, chloropyrazines including but not limited to L-687,306, L-689-660, 77-LH-28-1, LY593039, and any quiniclidine ring with oneor more carbon substitutions particularly that include an ester, sulfur,or 5 or 6 carbon ring structure including with substituted nitrogen(s)and or oxygen(s), or any pharmaceutically acceptable salts, esters,analogues, prodrugs or derivatives thereof. A preferred M1/M3 agonist isaceclidine. In a preferred embodiment, muscarinic agonist of the presentinvention include those muscarinic agonist that preferentially activateM1 and M3 over M2, M4, and M5; and even more preferably activate M1 overM3. In a more preferred embodiment muscarinic agonist of the presentinvention include those muscarinic agonist that only activate M1.

The term “aceclidine” encompasses its salts, esters, analogues, prodrugsand derivatives including, but not limited to, aceclidine as a racemicmixture, aceclidine (+) enantiomer, aceclidine (−) enantiomer,aceclidine analogues, including, but not limited to, highly M1 selective1,2,5 thiadiazole substituted analogues like those disclosed in Ward. J.S. et al., 1,2,5-Thiadiazole analogues of aceclidine as potent mlmuscarinic agonists, J Med Chem, 1998, January 29, 41(3), 379-392 andaceclidine prodrugs including but not limited to carbamate esters.

The term “pilocarpine” encompasses its salts, esters, analogues,prodrugs, derivatives and pilocarpine analogues.

The term “selective α-2 adrenergic receptor agonists” or “α-2 agonist”encompasses all α-2 adrenergic receptor agonists which have a bindingaffinity of 900 fold or greater for α-2 over α-1 adrenergic receptors,or 300 fold or greater for α-2a or α-2b over α-1 adrenergic receptors.The term also encompasses pharmaceutically acceptable salts, esters,prodrugs, and other derivatives of selective α-2 adrenergic receptoragonists.

The term “low concentrations” or “low-dose” refers to concentrationsfrom between about 0.0001% to about 0.065% w/v; more preferably, fromabout 0.001% to about 0.035% w/v; even more preferably, from about 0.01%to about 0.035% w/v; and even more preferably, from about 0.03% to about0.035% w/v.

The term “brimonidine” encompasses, without limitation, brimonidinesalts and other derivatives, and specifically includes, but is notlimited to, brimonidine tartrate,5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline D-tartrate, and Alphagan®.

The terms “treating” and “treatment” refer to reversing, alleviating,inhibiting, or slowing the progress of the disease, disorder, orcondition to which such terms apply, or one or more symptoms of suchdisease, disorder, or condition.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable (i.e. without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner).

As used herein, the term “pharmaceutically effective amount” refers toan amount sufficient to affect a desired biological effect, such as abeneficial result, including, without limitation, prevention,diminution, amelioration or elimination of signs or symptoms of adisease or disorder. Thus, the total amount of each active component ofthe pharmaceutical composition or method is sufficient to show ameaningful subject benefit. Thus, a “pharmaceutically effective amount”will depend upon the context in which it is being administered. Apharmaceutically effective amount may be administered in one or moreprophylactic or therapeutic administrations.

The term “prodrugs” refers to compounds, including, but not limited to,monomers and dimers of the compounds of the invention, which havecleavable groups and become, under physiological conditions, compoundswhich are pharmaceutically active in vivo.

As used herein “salts” refers to those salts which retain the biologicaleffectiveness and properties of the parent compounds and which are notbiologically or otherwise harmful at the dosage administered. Salts ofthe compounds of the present inventions may be prepared from inorganicor organic acids or bases.

The term “higher order aberrations” refers to aberrations in the visualfield selected from starbursts, halos (spherical aberration), doublevision, multiple images, smeared vision, coma and trefoil.

The term “cold chain” refers to storage at temperatures from about 2 toabout 8° C. from manufacture to immediately prior to administration.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids or bases. The phrase “pharmaceutically acceptable salt” meansthose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. For example, S. M. Berge etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66: 1 et seq.

The salts can be prepared in situ during the final isolation andpurification of the compounds of the invention or separately by reactinga free base function with a suitable organic acid. Representative acidaddition salts include, but are not limited to acetate, adipate,alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate, phosphate,glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, thebasic nitrogen-containing groups can be quaternized with such agents aslower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates; long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides; arylalkyl halides likebenzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,hyaluronic acid, malic acid, sulphuric acid and phosphoric acid and suchorganic acids as oxalic acid, malic acid, maleic acid, methanosulfonicacid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium and aluminum salts and the likeand nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylammonium,dimethylammonium, trimethylammonium, triethylammonium, diethylammonium,and ethylammonium among others. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, piperazine and the like.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, a heteroaryl group or other suitablesubstituent.

Compositions of the Invention

In one embodiment, the present invention is directed to anophthalmological composition comprising aceclidine. In a preferredembodiment, aceclidine is at a concentration from about 0.25% to about2.0% w/v, more preferably from about 0.50% to about 1.90% w/v, stillmore preferably from about 1.25% to about 1.85% w/v, and most preferablyfrom about 1.35% to about 1.65% w/v. As aceclidine is a tertiary aminewith asymmetry, both a + and − optical isomer exist (where in somestudies (+) is more potent and in others it is felt (−) may be morepotent). For the above concentrations polarimetry demonstrated anexactly equal ratio of (+) and (−) isomer for these concentrations.Altering this ratio could therefore alter this concentration rangeproportional to a change in ratio.

The present invention is further directed to an ophthalmologicalcomposition comprising a muscarinic agonist, preferably a nonionicsurfactant above its critical micellar concentration for thecomposition, and a viscosity enhancing agent; or alternatively an insitu gelling agent. In preferred embodiments the initial viscosity ofthe composition on topical application is above 20 cps, preferably 50cps, and more preferably above 70 cps at low shear (1/s).

Nonionic surfactants suitable for the present invention includecyclodextrins, polyoxyl alkyls, poloxamers or combinations thereof, andmay include in addition combinations with other nonionic surfactantssuch as polysorbates. Preferred embodiments include polyoxyl 40 stearateand optionally Poloxamer 188, Poloxamer 407, Polysorbate 20, Polysorbate80, ionically charged (e.g. anionic) beta-cyclodextrins with or withouta butyrated salt (Captisol®) 2-hydroxypropyl beta cyclodextrin(“HPβCD”), alpha cyclodextrins, gamma cyclodextrins, Polyoxyl 35 castoroil, and Polyoxyl 40 hydrogenated castor oil or combinations thereof.Further, substitution of other nonionic surfactants compatible withophthalmological use allows for similar formulation advantages, whichmay included but is not limited to one or more of a nonionizingsurfactant such as poloxamer, poloxamer 103, poloxamer 123, andpoloxamer 124, poloxamer 407, poloxamer 188, and poloxamer 338, anypoloxamer analogue or derivative, polysorbate, polysorbate 20,polysorbate 40, polysorbate 60, polysorbate 80, any polysorbate analogueor derivative, cyclodextrin, hydroxypropyl-β-cyclodextrin,hydroxypropyl-γ-cyclodextrin, randomly methylated β-cyclodextrin,β-cyclodextrin sulfobutyl ether, γ-cyclodextrin sulfobutyl ether orglucosyl-β-cyclodextrin, any cyclodextrin analogue or derivative,polyoxyethylene, polyoxypropylene glycol, an polysorbate analogue orderivative, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene(200), polyoxypropylene glycol (70), polyoxyethylene hydrogenated castoroil, polyoxyethylene hydrogenated castor oil 60, polyoxyl, polyoxylstearate, nonoxynol, octyphenol ethoxylates, nonyl phenol ethoxylates,capryols, lauroglycol, PEG, Brij® 35 (polyoxyethyleneglycol dodecylether; Brij is a registered trademark of Uniqema Americas LLC), glyceryllaurate, lauryl glucoside, decyl glucoside, or cetyl alcohol; orzwitterion surfactants such as palmitoyl carnitine, cocamide DEA,cocamide DEA derivatives cocamidopropyl betaine, or trimethyl glycinebetaine, N-2(2-acetamido)-2-aminoethane sulfonic acid (ACES),N-2-acetamido iminodiacetic acid (ADA),N,N-bis(2-hydroxyethyl)-2-aminoethane sulfonic acid (BES),2-[Bis-(2-hydroxyethyl)-amino]-2-hydroxymethyl-propane-1,3-diol(Bis-Tris), 3-cyclohexylamino-1-propane sulfonic acid (CAPS),2-cyclohexylamino-1-ethane sulfonic acid (CHES),N,N-bis(2-hydroxyethyl)-3-amino-2-hydroxypropane sulfonic acid (DIPSO),4-(2-hydroxyethyl)-1-piperazine propane sulfonic acid (EPPS),N-2-hydroxyethylpiperazine-N′-2-ethane sulfonic acid (HEPES),2-(N-morpholino)-ethane sulfonic acid (MES), 4-(N-morpholino)-butanesulfonic acid (MOBS), 2-(N-morpholino)-propane sulfonic acid (MOPS),3-morpholino-2-hydroxypropanesulfonic acid (MOPSO),1,4-piperazine-bis-(ethane sulfonic acid) (PIPES),piperazine-N,N′-bis(2-hydroxypropane sulfonic acid) (POPSO),N-tris(hydroxymethyl)methyl-2-aminopropane sulfonic acid (TAPS),N-[tris(hydroxymethyl)methyl]-3-amino-2-hydroxypropane sulfonic acid(TAPSO), N-tris(hydroxymethyl)methyl-2-aminoethane sulfonic acid (TES),2-Amino-2-hydroxymethyl-propane-1,3-diol (Tris), tyloxapol, and Span®20-80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, and sorbitan monooleate). In certain embodiments theaddition of an anionic surfactant such as sodium lauryl sulfate and orsodium ester lauryl sulfate may be preferred.

Ophthalmological in situ gels which may be substituted for or added inaddition to one or more nonionic surfactants include but are not limitedto gelatin, carbomers of various molecular weights including carbomer934 P and 974 P, xanthan gums, alginic acid (alginate), guar gums,locust bean gum, chitosan, pectins and other gelling agents well knownto experts in the art.

In preferred embodiments the nonionic surfactant is polyoxyl 40 stearateat a concentration from about 1 to about 15% w/v, more preferably atabout 5.5% w/v.

In such preferred embodiment, polyoxyl 40 stearate is found to enhancethe redness reduction effect preferentially over aqueous solutions andother nonionic surfactants such as poloxamer 407, particularly in thepresence of an α-2 agonist.

Viscosity enhancers suitable for the present invention include, but arenot limited to, guar gum, hydroxypropyl-guar (“hp-guar”), xanthan gum,alginate, chitosan, Gelrite®, hyauluronic acid, dextran, Carbopol®(polyacrylic acid or carbomer) including Carbopol® 900 series includingCarbopol® 940 (carbomer 940), Carbopol® 910 (carbomer 910) and Carbopol®934 (carbomer 934), carboxymethyl cellulose (“CMC”), methylcellulose,methyl cellulose 4000, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxyl propyl methyl cellulose 2906,carboxypropylmethyl cellulose, hydroxyethyl cellulose, or hydroxyethylcellulose, hyaluronic acid, dextran, polyethylene glycol, polyvinylalcohol, polyvinyl pyrrolidone, gellan, carrageenan, alignic acid,carboxyvinyl polymer or combinations thereof. In a preferred embodimentthe viscosity enhancer will have an equilibration viscosity less than100 cps, preferably from about 15 to about 35 cps, and most preferablyat about 30 cps. In a preferred embodiment the viscosity enhancer isCarbopol® 940 (carbomer 940) at a concentration from about 0.5% to about6.0% w/v, preferably from about 0.09% to about 1.0% w/v, more preferablyat 0.09%, 0.25%, 0.5%, 0.75%, 0.9% or 1.0% w/v. In certain combinationsit has been surprisingly discovered nonionic surfactant/viscositycombinations may result in phase separation over time with precipitateformation. In such situations, particularly for polyoxyls, in apreferred embodiment polyoxyl 40 stearate, and cellulose derivatives,particularly hydroxypropyl methyl cellulose, use of a nonpolysaccharidederivative for viscosity enhancement, such as polyacrylic acidderivatives (carbomers, carbomer 934 or 940 in preferred embodiments)may prevent such separation.

It is a discovery of the present invention that several modificationsmay singly or in combination be used to enhance cold chain stabilitystorage, including in addition to in a preferred embodiment aceclidine1.40%-1.75%, tropicamide 0.025%-0.10% and optionally a nonioinicsurfactant such as polyoxyl 40 stearate 0.5%-10%, preferably 5.5% one ormore of (See Table 1):

Acidic pH, preferably less than 5.5, preferably less than 5.0 and mostpreferably at a pH of about 4.75;

Viscosity enhancer, preferably at 25 C viscosity of about 15-50 cps, andmore preferably 20-35 cps, where a preferred embodiment is carbomer 9400.09%-1.0%;

Addition of a polyol, in a preferred embodiment Mannitol 2.5%-4.0%;

Addition of a buffer, where acetate or phosphate buffers are preferred,2-100 mmole range with 3-5 mmole is preferred;

Addition of a preservative, where BAK 0.02% is preferred or acombination of BAK, sorbate and borate.

The selective α-2 agonist may be included within the composition of thepresent invention or applied topically preferably just minutes before orless preferably just minutes afterward if additional means to reducenasal congestion or redness is desired for sensitive subjects. Selectiveα-2 agonists suitable for the present invention have minimal α-1 agonistactivity at low concentrations. For example, for brimonidine orfadolmidine, 1% to 2% w/v is considered extremely high, 0.5% to 1.0% w/vstill highly inductive of α-1 receptors and toxic for purposes of thepresent invention. Further, 0.10% to 0.5% w/v is still too high and even0.070% to 0.10% w/v is associated with a higher than preferred incidenceof rebound hyperemia (however, for dexmedetomidine, its greaterlipophilicity and intraocular penetration reduces rebound risk in thisrange). Only 0.065% w/v or below is potentially acceptable, where formost α-2 agonists, depending on degree of selectivity 0.050% w/v or evenmore preferably 0.035% w/v or less is desired. On the other hand somedegree of useful activity may occur at one or more orders of magnitudefurther reduction of concentration. The preferred embodiments,brimonidine, fadolmidine and guanfacine, of the present inventionpreferentially stimulate α-2 adrenergic receptors, and even morepreferably α-2b adrenergic receptors so that α-1 adrenergic receptorsare not stimulated sufficiently enough to cause excessive large vesselarteriolar constriction and vasoconstrictive ischemia. In addition, ithas been discovered that preventing or reducing redness for drugs thatotherwise directly induce redness, such as the acetylcholine agonist,aceclidine, enhances compliance for sensitive subjects that may haveinduced redness or nasal congestion even with formulations of thepresent invention that do not include an α-2 agonist. However, becauseα-2 agonists are shifted to their ionized equilibrium an acidic pH issomewhat offset by the fact such agonists exert greater affect atneutral or alkaline pH. Therefore each α-2 agonist has a preferred pHrange depending on its lipophilicity and pKa value when added to theinventive compositions with aceclidine. For the present invention whilepH range of 5.0 to 8.0 is tolerated, preferred embodiments are at pH 5.5to 7.5 and more preferably 6.5 to 7.0. Further, it has been discoveredthat cyclodextrins and/or polyoxyl 40 stearate as a nonionic surfactantcomponent or as the sole nonionic surfactant, result in a greaterwhitening effect when the α-2 agonist is included in the compositionrather than poloxamer 407. The α-2 agonist may optionally be appliedseparately or in certain preferred embodiments with formulations of thepresent invention that do not include an α-2 agonist, such as thoseformulas with polyoxyl 40 stearate 5.5% w/v as the non-ionic surfactant,although the α-2 agonist is not required except for occasional sensitivesubjects. Fadolmidine represents the α-2 agonist with highesthydrophilicity and therefore high surface retention for the presentinvention. Guanfacine is also highly selective and hydrophilic.Brimonidine is highly selective with moderate lipophilicity. Finally,dexmedetomidine has high selectivity with high lipophilicity that may beused with less efficacy for reducing redness for the purposes of thepresent invention (although possibly inducing fatigue as a side effectin some patients). In a preferred embodiment using polyoxyl 40 stearate5.5% w/v; CMC 0.80% w/v; NaCl 0.037% w/v; EDTA 0.015% w/v, borate buffer5 mM and BAK 0.007% w/v results in redness of about 1.0 to 1.5 out of 4which is transient lasting about ten minutes, and by 30 minutes returnsto about baseline.

In one embodiment, the selective α-2 adrenergic receptor agonist is acompound which has binding affinity of about 900 fold or greater, evenmore preferably about 1000 fold or greater, and most preferably, about1500 fold or greater.

The selective α-2 adrenergic receptor agonist may be present at aconcentration from between about 0.0001% to about 0.065% w/v; morepreferably, from about 0.001% to about 0.035% w/v; even more preferably,from about 0.01% to about 0.035% w/v; and even more preferably, fromabout 0.020% to about 0.035% w/v.

In one embodiment, the selective α-2 adrenergic receptor is selectedfrom the group consisting of brimonidine, guanfacine, fadolmidine,dexmedetomidine,(+)-(S)-4-[1-(2,3-dimethyl-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione,1-[(imidazolidin-2-yl)imino]indazole, and mixtures of these compounds.Analogues of these compounds that function as highly selective α-2agonists may also be used in compositions and methods of the presentinvention.

In a more preferred embodiment, the selective α-2 agonist is selectedfrom the group consisting of fadolmidine, guanfacine and brimonidine. Ina yet more preferred embodiment the selective α-2 agonist is brimonidinein the form of a salt at a concentration of 0.025% to 0.065% w/v, morepreferably from 0.03% to 0.035% w/v. In a preferred embodiment, the saltis a tartrate salt.

In another yet more preferred embodiment, the selective α-2 agonist isfadolmidine at a concentration from about 0.005% to about 0.05% w/v,more preferably from 0.02% to about 0.035% w/v in the form of ahydrochloride (“HCl”) salt.

In another yet more preferred embodiment, the selective α-2 agonist isguanfacine at a concentration from about 0.005% to about 0.05% w/v, morepreferably from 0.02% to about 0.035% w/v in the form of an HCl salt.

In another yet more preferred embodiment, the selective α-2 agonist isdexmedetomidine at a concentration from about 0.005% to about 0.05% w/v,more preferably from 0.04% to about 0.05% w/v in the form of an HClsalt.

In another preferred embodiment a pH less than physiologic pH is foundto enhance the whitening effect for brimonidine, preferably pH 4.5 to6.5, and more preferably pH 5.5 to 6.0. However, redness reduction isachieved at all pHs, and enhancement of aceclidine absorption occurs atalkaline pH, such that more effect occurs from a given concentration,and therefore while effective at pH ranges from 4.5 to 8.0, pH range of6.5 to 7.5 is preferred for the present invention, and 7.0 to 7.5 mostpreferred.

The present invention is further directed to an ophthalmologicalcomposition further comprising a cycloplegic agent. It is a surprisingand totally unexpected discovery of the present invention that certaincycloplegic agents can be combined with miotic agents, particularly forthe present invention, aceclidine, without reducing miotic onset,magnitude, or duration; and further blunt the normally attendant spikein miotic effect coinciding with time of peak absorption in aqueousformulations to provide a constant miosis versus time after onset from15 to 30 minutes to 6 to 10 hours depending on the desired formulation.The addition of the cycloplegic agent also reduces any residualassociated discomfort that may otherwise occur soon after topicalinstillation, which presumably is a result of ciliary spasms orexcessive pupillary miosis.

Cycloplegic agents suitable for the present invention include, but arenot limited to, atropine, Cyclogyl® (cyclopentolate hydrochloride),hyoscine, pirenzepine, tropicamide, atropine,4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), AF-DX 384,methoctramine, tripitramine, darifenacin, solifenacin (Vesicare®;Vesicare is a registered trademark of Astellas Pharma Inc.),tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium (Spriva),and otenzepad (a.k.a. AF-DX 116 or11-{[2-(diethylamino)methyl]-1-piperidinyl}acetyl]-5,11-dihydro-6H-pyrido[2,3b][1,4]benzodiazepine-6-one).In a preferred embodiment the cycloplegic agent is tropicamide at aconcentration from about 0.01% to about 0.10% w/v, more preferably fromabout 0.025% to about 0.080% w/v and still more preferably from about0.04% to about 0.06% w/v. In another preferred embodiment thecycloplegic agent is a mixture of tropicamide at a concentration fromabout 0.04% to about 0.07% w/v or pirenzepine or otenzepad at aconcentration from about 0.002% to about 0.05% w/v.

In a preferred embodiment, tropicamide 0.01% w/v was found to slightlyreduce brow ache, 0.030% w/v to further reduce brow ache and from 0.04%to about 0.07% w/v to completely eliminate brow ache without reductionof the average pupillary miosis diameter over duration of effect.Tropicamide in preferred embodiments has demonstrated completelyunexpected sensitivity of effect, where at about 0.04% w/v unexpectedlyand very effectively reduces or eliminates brow ache and ciliary spasmpain, becoming very noticeably further reduced at 0.042% w/v and absentat 0.044% w/v in a preferred embodiment with no cycloplegia (surprisingdue to its common use as a pupil dilating agent). Yet, tropicamide didnot reduce the mean degree of pupil miosis, the time of onset of pupilmiosis or the subsequent visual benefits. On the contrary, tropicamideblunted the peak miosis seen in aqueous formulations to create a smoothconsistent miotic effect over time. It allowed modulation of peak pupilmiosis to achieve a more even effect over time with no dilation as hasbeen found with its prior use. Specifically, tropicamide is useful toprevent transient constriction below 1.50 mm at 30 to 60 minutesfollowing aceclidine in some embodiments and to reduce transientexcessive and undesirable dimming of vision that may otherwise occur atpeak onset of about 30 minutes. As an example, an ophthalmologicalcomposition comprising 1.53% w/v aceclidine, 5% w/v HPβCD, 0.75% w/vCMC, 0.25% w/v NaCl, 0.01% w/v BAK and a phosphate buffer at pH 7.0; or1.45% w/v aceclidine; 5.5% w/v polyoxyl 40 stearate; 0.80% w/v CMC;0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK and 5 mM phosphatebuffer at a pH 7.0; was varied from 0.040% w/v tropicamide, wheremoderate dimming was noted, to 0.044% w/v tropicamide where dimmingbecame almost undetectable other than in extremely dim light conditions.This additional pupil size modulation with a cycloplegic agent allowsaceclidine or pilocarpine concentrations sufficient for prolonged effectwhile blunting the attendant peak excessive constriction that isundesirable as well as any uncomfortable brow ache. Surprisingly and dueto its short-acting nature, tropicamide achieves this blunting effectwithout causing mydriasis. Further, in a preferred embodiment,tropicamide 0.014% w/v was found to reduce brow ache, 0.021% w/v tofurther reduce brow ache and from 0.028% to 0.060% w/v and in someembodiments up to 0.09% w/v to completely eliminate brow ache withoutcycloplegia (i.e. paralysis of ciliary muscle of the eye).

It has been found for a racemic 50:50 mixture of (+) and (−) aceclidineoptical isomers (where in some studies (+) is more potent and in othersit is felt (−) may be more potent) tropicamide effects may varydepending on the ratio of aceclidine to tropicamide. For example, in anophthalmological composition of the present invention comprising 1.55%w/v aceclidine, 5.5% w/v HPβCD or in a preferred embodiment polyoxyl 40stearate, 0.75% w/v CMC (1%=2,500 centipoise), 0.25% w/v NaCl, and 0.01%w/v BAK and at pH 7.5, 0.042% w/v tropicamide can be differentiated fromeven 0.035% w/v, with the former demonstrating normal indoor nightvision and the latter slight dimming that becomes more noticeable atstill lower concentrations. At higher concentrations, such as from about0.075% to about 0.090% w/v tropicamide, loss of optimal range pupilconstriction 1.50 mm to 1.80 mm range begins, and frank mydriasis athigher concentrations begins to occur. As isomer ratio may alter theeffective concentration, this must be factored into the clinicalefficacy anticipated using aceclidine; for preferred embodiments of thepresent invention a polarimeter was used to determine an exact 50:50isomer ratio was used (personal communication Toronto ResearchChemicals).

FIG. 1 shows the effect of a miotic agent with or without a cycloplegicagent and with or without a carrier. Subject is an emmetrope over theage of 45 with a baseline near vision of 20.100 and baseline distancevision of 20.20. Topical administration to the eye of 1% w/v pilocarpinein saline solution results in an improvement of near vision to 20.40(8a), however this improvement comes at the expense of a reduction indistance vision to 20.100 (8b). The addition of 0.015% w/v tropicamideresults in an improvement of near vision to 20.25 (9a) and a lesseningof the reduction of distance vision to 20.55 (9b), though in certaininstances with some induced irregular astigmatism (mildly blotched areasin reading field of vision). Topical administration of 1.55% w/vaceclidine in saline solution results in an improvement of near visionto 20.40 for an extended time period of 6 hrs (10a) without any effecton the baseline distance vision (10b). 10c and 10d show the effects ofadministering aceclidine in a carrier composed of 5.5% w/v2-hydroxypropyl beta cyclodextrin, 0.75% w/v CMC (1%=2,500 centipoise),0.25% w/v NaCl, and 0.01% w/v BAK. As seen in 10c the carrier increasesthe beneficial effect of aceclidine resulting in better than 20.20 nearvision. As seen in 10d a similar increase in distance vision occurs. 10eand 10f show the effects of adding 0.042% w/v tropicamide to theaceclidine in the carrier. As seen in 10e near vision is improved to20.15 with a quicker onset of maximum visual acuity. As seen in 10f asimilar improvement is seen in distance vision. Taken together, FIG. 1shows that aceclidine is capable of temporarily correcting near visionin a presbyopic subject without affecting the baseline distance vision.Similar results can be achieved with a different miotic agent,pilocarpine, with the addition of a cycloplegic agent such astropicamide. A proper drug carrier can also have a beneficial effect.

The present invention is further directed to an ophthalmologicalcomposition further comprising a tonicity adjustor and a preservative.

A tonicity adjustor can be, without limitation, a salt such as sodiumchloride (“NaCl”), potassium chloride, mannitol or glycerin, or anotherpharmaceutically or ophthalmologically acceptable tonicity adjustor. Incertain embodiments the tonicity adjustor is 0.037% w/v NaCl,

Preservatives that can be used with the present invention include, butare not limited to, benzalkonium chloride (“BAK”), chlorobutanol,thimerosal, phenylmercuric acetate, disodium ethylenediaminetetraaceticacid, phenylmercuric nitrate, perborate or benzyl alcohol. In apreferred embodiment the preservative is BAK at a concentration of about0.001% to about 1.0% w/v, more preferably at a concentration of about0.007% w/v. In another preferred embodiment the preservative isperborate at a concentration of 0.01% to about 1.0% w/v, more preferablyat a concentration of about 0.02% w/v. In another preferred embodimentthe preservative is a combination of BAK, sorbate and borate.

Various buffers and means for adjusting pH can be used to prepareophthalmological compositions of the invention. Such buffers include,but are not limited to, acetate buffers, citrate buffers, phosphatebuffers and borate buffers. It is understood that acids or bases can beused to adjust the pH of the composition as needed, preferably of 1 to10 mM concentration, and more preferably about 5 mM. In a preferredembodiment the pH is from about 4.0 to about 8.0, more preferably fromabout 5.0 to about 7.0, even more preferably from about 5.0 to about 6.5and most preferred from about 5.0 to about 6.0.

The present invention is further directed to an ophthalmologicalcomposition further comprising an antioxidant. Antioxidants that can beused with the present invention include but are not limited to disodiumethylenediaminetetraacetic acid at a concentration from about 0.005% toabout 0.50% w/v, citrate at a concentration from about 0.01% to about0.3% w/w, dicalcium diethylenetriamine pentaacetic acid (“Ca2DTPA”) at aconcentration from about 0.001% to about 0.2% w/v, preferably about0.01% w/v Ca2DTPA which can be formulated by adding 0.0084% w/v Ca(OH)₂and 0.0032% w/v pentetic acid to the formulation and mixing slowly.Further combinations of antioxidants can be used. Other antioxidantsthat can be used with the present invention include those well known toexperts in the art such as ethylenediaminetetraacetic acid at aconcentration from about 0.0001% to about 0.015% w/v.

It is a surprising and unexpected discovery that topical formulations ofthe present invention, particularly one of the preferred embodimentscomprising aceclidine 1.35% to 1.55% w/v; 5.5% w/v polyoxyl 40 stearate;0.80% w/v CMC; 0.037% w/v NaCl; 0.015% w/v EDTA; 0.007% w/v BAK; and 5mM phosphate buffer at pH 7.0 result in considerably prolonged contactlens wear and comfort after a single topical instillation daily. Thesingle daily use of the preferred embodiments allowed a subject with dryeye to sleep in his lenses for one week periods where previously evenafter a single night vision would be blurred and contact lenses coatedwith film requiring removal and cleaning or replacement (see Example 7).

The following representative embodiments are provided solely forillustrative purposes and are not meant to limit the invention in anyway.

Representative Embodiments

In another embodiment, the ophthalmological composition comprises:

pilocarpine at a concentration of about 1.0% w/v;tropicamide at a concentration of about 0.012% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;carbomer 940 at a concentration of about 0.5% w/v;citric acid monohydrate at a concentration of about 0.1% w/v; andacetate buffer at a concentration of about 3 millimolar,wherein said composition has a pH of about 5.

In another embodiment, the ophthalmological composition comprises:

pilocarpine at a concentration of about 0.95% w/v;tropicamide at a concentration of about 0.012% w/v or about 0.015% w/v;polyoxyl 40 stearate at a concentration of about 3.85% w/v;carbomer 940 at a concentration of about 0.50% w/v;citric acid monohydrate at a concentration of about 0.1% w/v; andacetate buffer at a concentration of about 3.0 millimolar,wherein said composition has a pH of about 5.

In another embodiment, the ophthalmological composition comprises:

pilocarpine at a concentration of about 1.50% w/v;tropicamide at a concentration of about 0.035% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;carbomer 940 at a concentration of about 0.385% w/v or about 0.85% w/v;citric acid monohydrate at a concentration of about 0.1% w/v; andacetate buffer at a concentration of about 3.0 millimolar,wherein said composition has a pH of about 5.

In another embodiment, the ophthalmological composition comprises:

pilocarpine at a concentration of about 1.50% w/v;tropicamide at a concentration of about 0.038% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;carbomer 940 at a concentration of about 0.385% w/v or about 0.85% w/v;citric acid monohydrate at a concentration of about 0.1% w/v; andacetate buffer at a concentration of about 3.0 millimolar,wherein said composition has a pH of about 5.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.75% w/v;tropicamide at a concentration of about 0.042% w/v;polyoxyl 40 stearate at a concentration of about 4.5% w/v;mannitol at a concentration of about 2.5% w/v;acetate buffer at a concentration of about 3.0 mM; andBAK at a concentration of about 0.02% w/v,wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.55% w/v;tropicamide at a concentration of about 0.042% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;citric acid monohydrate at a concentration of about 0.1% w/v;mannitol at a concentration of about 4.0% w/v;Carbopol® (carbomer) 940 at a concentration of 0.09% w/v; andacetate buffer at a concentration of about 3.0 mM;wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.50% w/v;tropicamide at a concentration of about 0.042% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;mannitol at a concentration of about 2.5% w/v;phosphate buffer at a concentration of about 3.0 mM;Carbopol® (carbomer) 940 at a concentration of about 0.25% w/v; andBAK at a concentration of about 0.02% w/v,wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.45% w/v;tropicamide at a concentration of about 0.042% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;mannitol at a concentration of about 4.0% w/v;citric acid monohydrate at a concentration of about 0.1% w/v;acetate buffer at a concentration of about 3.0 mM; andCarbopol® (carbomer) 940 at a concentration of about 0.75% w/v,wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of about 1.45% w/v;tropicamide at a concentration of about 0.042% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;mannitol at a concentration of about 4.0% w/v;citric acid monohydrate at a concentration of about 0.1% w/v;phosphate buffer at a concentration of about 3.0 mM; andCarbopol® (carbomer) 940 at a concentration of about 1.0% w/v,wherein said composition has a pH of about 4.75.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.5% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.55% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.6% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.65% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.7% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.75% w/v, mannitol at a concentrationof 2.5% w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.48% w/v, mannitol at a concentrationof 4.0% w/v and Carbopol® (carbomer) 940 at a concentration of 0.09%w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.48% w/v, mannitol at a concentrationof 4.0% w/v and Carbopol® (carbomer) 940 at a concentration of 0.50%w/v.

In another embodiment, the ophthalmological composition comprises:

aceclidine at a concentration of 1.48% w/v, mannitol at a concentrationof 2.5% w/v and Carbopol® (carbomer) 940 at a concentration of 0.09%w/v.

The following Examples are provided solely for illustrative purposes andare not meant to limit the invention in any way.

EXAMPLES Example 1 Effect of Aceclidine on Vision of Subjects Aged 47 to67 Years

Table 1 demonstrates the effect on the near focus ability of presbyopicsubjects before and after ophthalmological administration of acomposition containing aceclidine. Each composition included aceclidinein the concentrations indicated and 5.5% w/v HPβCD, 0.75% w/v CMC, 0.25%w/v NaCl and 0.01% w/v BAK. Additionally compositions administered tosubjects 4 and 5 included 0.125% w/v tropicamide. As aceclidine is anenantiomer, the clinical effectiveness may vary with different ratios.For the present studies a nearly exact 50:50 ratio of stereoisomers wasmeasured as best determined by polarimetry.

TABLE 1 Effects of aceclidine on vision of presbyopic patients. VisionBaseline Post Gtt 15″ Aceclidine R Pre L Pre R Pre L Pre R Post L Post RPost L Post Effect Date # Age % Dist Dist Near Near Dist Dist Near Near(h) Aug. 21, 2013 1 67 1.5 20.20 20.30 20.60 20.60 20.20 20.20 20.1520.15 9.00 Aug. 22, 2013 2 52 1.5 20.30 20.30 20.50 20.50 20.25 20.2520.25 20.20 8.00 Aug. 23, 2013 3 61 1.5 20.40 20.30 20.60 20.50 20.2020.25 20.15 20.15 8.00 Aug. 23, 2013 4 61 1.1 20.20 20.25 20.80 20.5020.15 20.15 20.20 20.15 12.00 Aug. 23, 2013 5 53 1.1 20.20 20.20 20.6020.60 20.20 20.20 20.25 20.25 7.00 Aug. 24, 2013 6 47 1.5 20.25 20.2520.100 20.100 20.20 20.20 20.15 20.15 8.00 Aug. 25, 2013 7 58 1.5 20.3020.200 20.100 20.30 20.25 20.30 20.20 20.30 8.00

As seen in Table 1 all subjects had less than perfect near vision(20.20) in both the left and right eye (object at 15 inches from theeye) and most subjects had less than perfect distance vision beforeadministration of the composition. After administration of thecomposition all subjects experienced an improvement in their near visionthat lasted from 7 to 12 hours. Surprisingly, the majority of subjectsalso experienced improvement of their distance vision for the same timeperiod. Still more surprisingly the improvement in near point was muchcloser than 16″ typically required for comfortable reading, in somecases to about 8.5″ more commonly seen in individuals 30 or less. Theaddition of tropicamide, a cycloplegic agent, had no additive ordeleterious effect on vision correction.

Example 2 Effect of Concentration of Concentration of Aceclidine andTropicamide

TABLE 2 Effect of concentration of concentration of aceclidine andtropicamide. #1 #2 #3 #4 #5 (OD) #5 (OS) #6 #7 Brimonidine 0.03% 0.03%0.03% 0.03% 0.03% 0.03% 0.03% Poloxamer 407  5.5% HPBCD  5.5%  5.5% 5.5%  5.5%  5.5%  5.5%  5.5% Aceclidine  1.5%  1.5% 0.75%  1.1%  1.1% 1.1%  1.1%  1.1% Tropicamide 0.014%  0.021%  0.028%  0.042%  0.062% NaCl 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% 0.25% CMC 0.75% 0.75%0.75% 0.75% 0.75% 0.75% 0.75% 0.75% BAK  0.1%  0.1%  0.1%  0.1%  0.1% 0.1%  0.1%  0.1% Redness (15 m) 3+  1   0.5 0.5 0 0 0 0 Redness (30 m)1.5 0.5 0.25 0.25 0 0 0 0 Brow Ache 2+  2+  2 0.5 0.5 0.0 0.0 0.0 (60 m)Stinging (10 m) 2   2   0.5 0 0 0 0 0 BD-OD 20.20 20.20 20.20 20.2020.20 20.20 20.20 20.20 BD-OS 20.25 20.25 20.25 20.25 20.25 20.25 20.2520.25 BN-OD 8 pt  8 pt  8 pt  8 pt  8 pt  8 pt  8 pt  8 pt  BN-OS 7 pt 7 pt  7 pt  7 pt  7 pt  7 pt  7 pt  7 pt  BP-photopic 3 mm 3 mm 3 mm 3mm 3 mm 3 mm 3 mm 3 mm BP-mesopic 5 mm 5 mm 5 mm 5 mm 5 mm 5 mm 5 mm 5mm Miosis start (m) 15   15   15 15 15 15 15 15 Miosis (OU) 1.63 mm  1.63 mm   2.0-2.5 mm    1.63 mm   1.63 mm   1.63 mm   1.63 mm   1.70mm   (1 hr) Distance (OU) 20.20 20.20 20.20 20.20 20.20 20.20 20.2020.20 (20 m) Distance (OD) 20.15 + 2 20.15 + 2 20.20 20.15 + 2 20.15 + 220.15 + 2 20.15 + 2 20.15 + 2 (1 hr) Distance (OS) 20.15 + 2 20.15 + 220.20 20.15 + 2 20.15 + 2 20.15 + 2 20.15 + 2 20.15 + 2 (1 hr) Disance(OU) 20.10 − 3 20.10 − 3 20.15 20.10 − 3 20.10 − 3 20.10 − 3 20.10 − 320.10 − 3 (1 hr) Near (OU) (20 m) 4 pt  4 pt  4pt 4 pt  4 pt  4 pt  4pt  4 pt  Time (hr) 12.5  12.5  6.5 11 10 10 Abbreviations: (C)indicates corrected vision, (m) indicates minutes, (hr) indicates hour,mm indicates millimeters, BD indicates baseline distance vision; BNindicates baseline near vision, BP indicates baseline pupil size, ODindicates right eye; OS indicates left eye and OU indicates both eyes.

All percentages are w/v. “pt” reflects size of print materials, 4 beingequivalent to 20/20 vision and 3 to 20/15 vision.

“Time” refers to duration of the effect.

As seen in Table 2 aceclidine at a concentration of at least 1.1% w/vwas able to reduce the size of the pupil to 1.63 mm 1 hour after topicalinstillation resulting in corrected near and distance vision for atleast 10 hours. Lowering of the concentration of aceclidine to 0.75% w/v(formula #3) reduced the miotic effect to 2.0-2.5 mm after 1 hour andvision correction lasted only 6.5 hours. The addition of 0.03% w/vbrimonidine reduced redness of the eye (4 out of 4 without brimonidine,not shown) to 1.5 out of 4 within 30 minutes after topical instillationwhich was maintained for the entire time vision was corrected. Switchingthe nonionic surfactant to HPβCD (formulas #2-6) further reduced theredness of the eye. Lowering of the concentration of aceclidine to 0.75%w/v (formula #3) further reduced eye redness but as mention above alsoreduced the vision correction duration of the formula.

A brow ache and stinging in the eye were noticeable in formulas #1-3with a 2 out of 4 level of pain which was also associated with feelingsof slight nausea, upset stomach and fatigue. Surprisingly, the additionof a cycloplegic agent, tropicamide, reduced brow ache and stinging to0.5 out of 4 and 0 out of 4 respectively with brow ache dissipatingafter 60 minutes (formula #4). Further, the raising of the concentrationof aceclidine to 1.1% w/v restored the longer duration of correctedvision seen in formulas #1-2 without increasing eye redness. However,upon re-topical instillation of formula #4 at the end of the 10 hoursnoticeable brow ache occurred. Topical instillation of formula #5 (OD)and (OS), with increased tropicamide concentrations, following formula#4 relieved the brow ache experienced with re-installation of formula#4. Upon a 3^(rd) topical instillation, at the end of the effectiveduration of formula #5, re-topical instillation of formula #5 again ledto considerable brow ache. Once again, in formula #6, raising theconcentration of tropicamide was able to overcome the brow ache.Additionally and unexpectedly, tropicamide, despite being a cycloplegicagent, had no effect on pupil miosis or vision correction. Surprisingly,the addition of tropicamide resulted in a prolonged duration of optimalpupil size constriction.

To determine the effect of brimonidine on pupil miosis, formula #7, wasadministered. Administration of formula #7 resulted in only a slightdecrease in pupil miosis to 1.70 mm with identical distance and nearvision improvement to that of formula #5. A 2-3+ conjunctival injectionwas noted.

All baseline vision data was based on vision corrected with distancecontact lenses. Near vision was noted by subject as outstanding from 8inches to the horizon at 1.5 hours after installation. A MarcoAutorefractor with infrared camera and superimposed pupil calibrationscale was used for all pupil size measurements. Once an image wasselected it remained on screen allowing accurate calibration.

Example 3 Effect of Concentration of Aceclidine, Brimonidine,Guanfacine, Fadolmidine, Tropicamide and Additives

TABLE 3 Effect of concentration of aceclidine, brimonidine, guanfacine,fadolmidine, tropicamide and additives. AB2T AB4T AB6T AB11T AB12TPROPH13 Aceclidine 1.55 1.55 1.55 1.55 1.85 1.55 Brimonidine 0.037 0.0370.037 0.037 Fadolmidine 0.037 Guanfacine 0.037 HPBCD 5.5 5.5 5.5 5.5 5.55 Tropicamide 0.043 0.043 0.043 0.043 0.042 0.043 CMC* 0.075 0.075 0.0750.075 0.075 0.075 NaCl 0.025 0.025 0.025 0.025 0.025 0.025 BAK 0.01 0.010.01 0.01 0.01 0.01 Glycerin 0.1 0.1 0.1 Poloxamer 188 0.1 0.05 Polyoxyl40 stearate 0.05 pH 6.5 7.5 7.5 7.5 7.0 7.5 nasal congestion 0 0 0 0 0 0stinging initial 0.75 0 1.5 3.5 0 1.5 stinging, 3 min 0.5 0 0 wash out 00 redness initial 0 0 1 D/C 1 1 redness 15 min 0 0 0 D/C 0 0 whitening 00 0 D/C 1.5 1.5 pain 0 0 0 D/C 0 0 vision near 20.30 20.15 20.15 D/C20.15 20.15 vision distance 20.20 20.20 20.20 D/C 20.20 20.20 onset(min) 20 12 16 D/C 12 16 duration (hrs) 5.5 7.5 7.5 D/C 7.5 7.5 colorclear yellow yellow yellow yellow yellow OVERALL 2.5 3.9 3.8 0 4 3.9 *1%= 2,500 cps

All percentages are w/v. Scores for nasal congestion, stinging initial,stinging, 3 min, redness initial, redness 15 min, whitening, pain andoverall are out of 4.

“pt” reflects size of print materials, 4 being equivalent to 20/20vision and 3 to 20/15 vision.

Baseline vision was 20.20 both eyes for distance; 20.70 right eyeunaided for near; 20.80 left eye for near (best @ 16″).

D/C stands for discontinued after eye washing due to intolerablestinging.

Aceclidine at a concentration of 1.55% w/v was able to reduce the sizeof the pupil to about 1.63 mm 30 minutes after topical instillationresulting in corrected near and distance vision to 20.20 or better forat least 6 hours, with noticeable affect lasting about 7.5 hours as seenin Table 3. Lowering of the concentration of aceclidine to 1.25% w/v(not shown) resulted in useful near vision improvement to about20.25-20.30, but not as effective as at the higher dose range alkalinepH resulted in quicker onset, longer duration, and greater effect. Theaddition of 0.037% w/v brimonidine reduced redness of the eye (4 out of4 without brimonidine, not shown) to baseline within 15 minutes aftertopical instillation which was maintained for the about the entire timevision was corrected. Adding glycerin 0.10% w/v noticeably reducedstinging. Adding instead poloxamer 188 0.05% w/v and polyoxyl 40stearate 0.05% w/v however reduced initial stinging further but was moreviscous. The combination of glycerin 0.1% w/v, poloxamer 188 0.1% w/v ata pH of 6.5 was noticeably reduced in onset, duration, comfort andeffectiveness. AB11T did not include glycerin, poloxamer 188, orpolyoxyl 40 stearate, which resulted in substantial stinging anddiscontinuation of the experiment with eye flush irrigation immediatelyafter topical instillation. Substitution of guanfacine 0.037% w/v inAB12T for brimonidine resulted in minimal initial redness with prolongedredness reduction and some degree of whitening, and appeared to provideoverall the best cosmesis though requiring slightly higher aceclidineconcentration for optimal effect.

All baseline vision data was based on vision corrected with distancecontact lenses. Near vision was noted by subject as outstanding from 8to 10 inches to the horizon at 30 minutes after installation for AB4Tand AB6T.

AB4T and AB6T were repeated both monocularly and binocularly.Substantial improvement in depth perception, near point acuity to 3 pt(20.15), and near point distance (8″, 20.20) was noted when both eyeswere treated vs. monocular treatment. Monocular treatment resulted inworsening of vision with both eyes open versus testing only the treatedeye.

Example 4 Effect of Concentration of Aceclidine, Brimonidine,Tropicamide, and Additives

TABLE 4 Effect of concentration of aceclidine, brimonidine, tropicamide,and additives. #8 #9 #10 #11 #12 #13 #14 Aceclidine 1.61% 1.61% 1.61%1.61% 1.61% 1.53% 1.53% Tropicamide 0.042%  0.042%  0.042%  0.042% 0.042%  0.044%  0.044%  Brimonidine 0.042%  0.042%  0.042%  0.042% 0.042%  CMC 0.75% 0.75% 0.80% 0.87% 0.75% 0.75% 0.75% NaCl 0.25% 0.25%0.50% 0.50% 0.25% 0.50% 0.50% BAK 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%0.01% pH 7.00 7.00 7.00 7.00 8.00 7.00 7.00 phosphate buffer 5 mM 5 mM 5mM 6 mM 5 mM 5 mM borate buffer 5 mM Onset (min) 15 15 15 15 15 15 15Duration (hrs) 7 7 10-12 10-12 7 9 7 Pupil range (mm) 1.5-1.7 1.5-1.71.5-1.7 1.5-1.7 1.5-1.7 1.8-2.0 1.8-2.0 Dimming 0-4 1.5 1.5 1.5 1.5 1.50.5 0.5 Sting 0-4 1 1 1 1 1 1 1 Ache 0-4 0.25 0.25 0.25 0.25 0.25 0.000.00 Redness 0-4 0.5 0.5 0.5 0.5 1.5 1.0 0.5 Other watery watery slthicker sl residue watery watery watery Overall 0-5 3.5 3.5 4 4 2.5 4.54.75 #15 #16 #17 #18 #19 #20 #21 Aceclidine 1.53% 1.53% 1.53% 1.53%1.45% 1.65% 1.75% Tropicamide 0.044%  0.044%  0.044%  0.044%  0.042% 0.044%  0.035%  Brimonidine 0.042%  0.042%  0.042%  0.042%  0.042% 0.042%  CMC 0.80% 0.80% 0.80% 0.80% 0.75% 0.75% 0.75% NaCl 0.50% 0.75%0.75% 1.00% 0.25% 0.25% 0.25% BAK 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%0.01% pH 7.00 7.00 8.00 7.00 7.00 7.00 8.00 phosphate buffer 5 mM 5 mM 5mM 5 mM 5 mM 5 mM 6 mM borate buffer Onset (min) 15 15 15 15 15 15 15Duration (hrs) 10-12 9 9 7 7 7 7 Pupil range (mm) 1.8-2.0 1.8-2.01.8-2.0 1.8-2.0 1.8-2.1 1.8-2.1 1.8-2.2 Dimming 0-4 0.5 0.5 0.5 0.5 0.50.5 0.5 Sting 0-4 1 1 1 1 1 1 1 Ache 0-4 0.00 0.00 0.00 0.00 0.00 0.250.00 Redness 0-4 0.5 0.5 1.0 0.5 0.5 0.5 0.5 Other sl thicker sl thickersl thicker thicker watery watery watery Overall 0-5 5 5 5 4 4 4 4

As seen in Table 4, formulas #8-9, an increase in brimonidine to 0.42%w/v resulted in redness reduction to 0.5, while 0.75% w/v CMC resultedin a watery consistency. Unexpectedly, increasing CMC from 0.75% w/v toa range of 0.80% w/v to 0.87% w/v and increasing NaCl from 0.25% w/v to0.75% w/v in formulas #10-11 resulted in a thicker consistency and anincreased residence time from 7 hours to 10-12 hours and decreased theamount of drug that drained into the nasolacrimal duct. This decreaseddrug delivery to the nasal passages results in less nasal congestion.

In formulas #13-18 a decrease in the amount of aceclidine from 1.61% to1.53% w/v resulted in a pupil size range from 1.8-2.0 mm. Dimming as aresult of the restriction of the pupil decreased linearly from 1.5 to0.5 with the decreased amount of aceclidine. Specifically, the 1.8 to2.0 mm pupil created 41% more light than the 1.5 to 1.7 mm pupil.Surprisingly, the 1.8 to 2.0 mm pupil had a near depth increase of 1.75D. This is only a 0.25 D loss from the beneficial 2.00 D seen with the1.5-1.7 mm range. Thus, the 1.80 to 2.0 mm range produces 41% more lightwhile still allowing the full benefit of increased near vision inindividuals under 60 years of age; whereas, individuals 60 years of ageand over still experience total computer benefit and some increased nearbenefit.

The increase in tropicamide concentration from 0.042% w/v (formulas#8-#11) to 0.044% w/v (formulas #13-#18) resulted in a decrease in acheto negligible amounts. The amount of ache may also be correlated withthe age of the individual. For those individuals under the age of 45, anincrease of tropicamide concentration to a range from 0.046% to 0.060%w/v may be preferred.

Further, Table 4 shows an unexpected result seen in formulas #13 and #17where the increase of NaCl from 0.25% w/v to a range of 0.50 to 0.75%w/v resulted in an acceptable redness score of only 1.0 even without theaddition of the redness reducing agent brimonidine.

Formulas #15, #16 and #17 each result in an overall maximum rating of 5by combining the benefits of: (1) reduced aceclidine concentrations toimprove the amount of light produced without significantly affecting thenear vision benefits seen in formulas #8-#12; (2) increased NaClconcentrations resulting in a further reduction in redness even in theabsence of brimonidine; and (3) increased CMC concentrations resultingin longer residency time on the eye.

Formula #19 is an excellent alternative for the minority of individualsthat are high responders to formulas #15-#17 and get noticeable dimmingwith 1.53% w/v aceclidine. Formula #20 is an excellent alternative forthe minority of individuals that are low responders to formula #19.Lastly, Formula #21 is an excellent alternative for the minority ofindividuals that are low responders and get poor pupil response withFormula #20.

Example 5 Comparison of Effects of Polyoxyl 40 Stearate, HPβCD andPoloxamer 407

TABLE 5 Comparison of Effects of Polyoxyl 40 Stearate, HPβCD andPoloxamer 407. #22 #23 #24 Aceclidine  1.45%  1.45%  1.45% Tropic amide0.044% 0.044% 0.044% Brimonidine 0.040% 0.040% 0.040% Polyoxyl 40Stearate  5.5% HPβCD  5.5% Poloxamer 407  5.5% CMC  0.80%  0.80%  0.80%NaCl 0.037% 0.037% 0.037% EDTA 0.015% 0.015% 0.015% BAK 0.007% 0.007%0.007% pH 7.00 7.00 7.00 phosphate buffer    5 mM    5 mM    5 mM NasalCongestion 0.00 0.50 1.50 Stinging 0.25 0.25 0.25 Wetting 4.00 4.00 4.00Redness 0.25 0.50 0.50 Visual Blur (<15 sec) 0.50 0.50 1.50 Duration 6-8hrs  6-8 hrs  6-8 hrs  Overall 0-4 4.00 4.00 4.00

Clinical Protocol

20 presbyopic patients with full distance correction were each given oneof the above formulas (#22-#23). All patients received pre- andpost-drop distance and near acuity measurement, Zeiss Visante® (Visanteis a registered trademark of Carl Zeiss Meditec AG) optical adherencetomography, axial length and contrast acuity testing (i.e.Colenbrander-Michelson 10% Lum target) with the following results:

-   -   all patient achieved a miotic pupil of 1.5 to 2.20 mm;    -   no patient experienced ciliary ache, ciliary spasm, or induced        accommodation;    -   all patients achieved 20/30+ visual acuity or better at 14″ and        were very satisfied with their high contrast near vision results        and there was no significant complaint of burning or aching;    -   the duration of effect lasted 6-8 hrs in all cases;    -   binocular vision afforded all patients 1-1.5 additional lines of        near acuity over monocular testing;    -   the last 10 patients were tested at 20″ (i.e. computer distance,        cell phone distance) and all achieved 20/25 or better near        visual acuity;    -   moderately hyperopic (approx. +2.25 sphere) uncorrected        presbyopes were very satisfied with distance visual acuity that        improved to a 20/25 or better level at distance and near vision        in the 20/30 range; and    -   uncorrected distance acuity was often improved for those        patients who chose not to routinely correct a small refractive        error.

As seen in Table 5, the use of polyoxyl 40 stearate provides the mostcomfortable aceclidine formulation with the least amount of visual blurand redness. To achieve similar results to that of formula #22, formula#23 requires 10-15% higher concentrations of the non-ionic surfactantand formula #24 requires 15-20% higher concentrations of the non-ionicsurfactant. HPBCD induced a color change over time, possibly indicativeof oxidation. Captisol® (sulfobutylether β-cyclodextrin) was substitutedwith similar findings.

Example 6 Modulation of Aceclidine Concentrations in a PreferredEmbodiment Preferred Embodiment

-   -   Aceclidine 1.35%-1.55% w/v;    -   Polyoxyl 40 stearate 5.5% w/v;    -   NaCl 0.037% w/v;    -   a viscosity enhancer, preferably CMC 0.80% w/v or an amount of        Carbopol® 934 or 940 sufficient to achieve a viscosity of from        about 5 to about 35 cps upon topical instillation, such as        Carbopol® 940 at a concentration from about 0.09% to about 1.0%        w/v;    -   BAK 0.02% w/v; and    -   a phosphate, citrate, citrophosphate, or acetate buffer from        about 3 to about 10 mM,    -   wherein the pH is from about 4.75 to about 6.0.

For 1.35% w/v aceclidine—

Stinging on topical instillation 0.25/4.0 (lasting about 2-5 seconds);Induced redness at 10 minutes: 1.0 to 1.5/4.0;Induced redness at 30 minutes: 0.0 to 0.25/4.0;Comfort: very high.Wetting: very high, the eye maintaining sensation of improved wettingfor most of a 24 hour period after a single topical instillation.Depth of Focus distance: excellent.Depth of Focus near: excellent.

In testing the above formulations on several subjects it was discoveredthat there is a slight range in clinical effect depending on theconcentration of aceclidine, where 1.35%-1.55% w/v aceclidine ispreferred, but for which 1.35% w/v and 1.45% w/v confer the desiredbenefits on most subjects.

Further, it is discovered that the clinical effect of 1.35% w/vaceclidine can be improved when instilled as follows:

-   -   1) baseline effect: 1 drop to each eye.    -   2) enhanced effect: 2 drops to each eye.    -   3) greater effect: after 2) above repeat 1) above.    -   4) maximum effect: after 2) above repeat 2) above.

Example 7 Use of a Preferred Embodiment to Prolong Contact Lens WearPreferred Embodiment

-   -   Aceclidine 1.45% w/v;    -   Polyoxyl 40 stearate 5.5% w/v;    -   NaCl 0.037% w/v;    -   a viscosity enhancer, preferably CMC 0.80% w/v or an amount of        Carbopol® 934 or 940 sufficient to achieve a viscosity of from        about 5 to about 35 cps upon topical instillation, such as        Carbopol® 940 at a concentration from about 0.09% to about 1.0%        w/v; BAK 0.02% w/v; and    -   a phosphate, citrate, citrophosphate, or acetate buffer from        about 3 to about 10 mM,    -   wherein the pH is from about 4.75 to about 6.0.

As a baseline, the subject, who normally wore extended wear lenses (AirOptix®; Air Optix is a registered trademark of Novartis AG) for dailywear only, slept in these lenses overnight. On arising each morning thesubject's vision was blurred and the contact lenses required removal andcleaning of film and deposits that had formed overnight. Average visionon arising at distance: 20.60; average vision at near on a Michelsoncontrast acuity chart: 20.80.

Then, for seven consecutive days the above formulation was instilledbetween 7 am and 10 am each day as a single dose. Subject wore the AirOptix® lenses throughout each day and slept in the lenses overnight.Upon arising each morning the subject's vision at distance: 20.20+;vision at near 20.40 unaided (consistent with subject's baselinepresbyopia when the subject did not wear the lenses overnight andinstead inserted the lenses upon arising).

Example 8 Comparison of Effects of Polyoxyl 40 Stearate and Captisol®(Sulfobutylether β-Cyclodextrin

TABLE 6 Comparison of Effects of Polyoxyl 40 Stearate and Captisol ®(sulfobutylether β-cyclodextrin). #25 #26 #27 #28 #29 #30 #31 #32 #33Aceclidine  1.35%  1.35%  1.35%  1.35%  1.35%  1.35%  1.35%  1.35% 1.35% Tropicamide 0.044% 0.044% 0.044% 0.044% 0.044% 0.044% 0.044%0.044% 0.044% Polyoxyl 40 stearate  5.5%  5.5%  5.5%  5.5%  5.5%  5.5% 5.5% Captisol ®  5.5%  5.5% Cocamidopropyl betaine  0.10% EDTA 0.015%0.015% 0.005% 0.005% 0.005% 0.005% 0.015% CMC 1% = 2,500 cps  0.80% 0.80%  0.80%  0.80%  0.80%  0.80%  0.80%  0.80%  0.80% NaCl 0.037%0.037% 0.037% 0.037% 0.037% 0.037% 0.037% 0.037% 0.037% Mannitol    4%   4% BAK 0.007% 0.007% 0.007% 0.007% 0.007% 0.007% 0.007% 0.007% 0.007%Borate buffer (mM) 4 4 4 4 4 4 4 Phosphate buffer (mM) 4 4 PH 7 7 7 7 77 7 7 7 Redness, 10 min 1.25 1.25 2 2 1.75 1.75 0 0 0 Redness, 30 min 00 1.5 1.5 1.25 1.25 0 0 0 Pupil, 30 min (mm) <2 <2 <2 <2 <2 <2 <2 <2 <3Blur on instill (sec) 10 10 10 10 10 10 10 10 10 Ache 0 0 0 0 0 0 1 0 0Rating 4.00 4.00 2.00 2.00 2.50 2.50 1.00 5.00 TBD

As seen in Table 6, when using polyoxyl 40 stearate as the surfactantthe exclusion of EDTA results in reduced redness and best overall ratingamong polyoxyl 40 stearate compositions (Formulas #25 and #26). Theaddition of cocamidopropyl betaine (“CAPB”) further reduces rednesshowever results in significant ache (Formula #31). Replacing polyoxyl 40stearate with Captisol® (sulfobutylether β-cyclodextrin) and addingmannitol achieves similar results in redness reduction as the additionof CAPB to polyoxyl 40 stearate but without the attendant ache resultingin the highest overall rating among aceclidine compositions (Formula#32). After several weeks formulations with Captisol® (sulfobutyletherβ-cyclodextrin) had an orange hue, possibly indicative of oxidation.

Example 9 Preferred Cold Chain Composition

Composition

-   -   aceclidine at a concentration of about 1.40%-1.80% w/v; and    -   tropicamide at about 0.42% w/v;    -   polyoxyl 40 stearate at about 5.5% w/v;    -   mannitol at a concentration of about 2.5% to 4.5% w/v;    -   carbomer 940 at a concentration of about 0.09% to about 2.0%        w/v;    -   optionally, a preservative such as BAK at a concentration of        about 0.2% w/v;    -   optionally citrate at a concentration of about 0.1%;    -   optionally with acetate or phosphate buffer at 2-100 mM, more        preferably 3-5 mM    -   wherein said composition has a pH of about 4.50 to about 5.0;        and preferably, about 4.75 to about 5.0; and    -   wherein w/v denotes weight by volume

A composition as described above was administered to a 62 year oldsubject. It resulted in pupils of 1.8-1.9 mm ou, 20.20+reading vision,and 20.20+distance vision; whereas without carbomer 940 reducedeffectiveness resulted at 2.5% mannitol and no near vision effectresulted at 4.0% mannitol. No ciliary spasm or loss of distance visionresulted. Onset was within about 15 minutes. Transient redness of about1+/out of 4 was noted for about 20 minutes without alpha agonistvasoconstrictor. The presence or absence of BAK had no clinical effect,and was used to provide an optional preservative.

Example 10 Stabile Aceclidine Formulations

Composition Tested:

aceclidine at a concentration of about 1.50% w/v;tropicamide at a concentration of about 0.042% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;mannitol at a concentration of about 2.5% w/v;citrate at a concentration of about 3 mM;wherein said composition has a pH of about 4.75.

20 samples of the above composition were divided evenly and stored at25° C. and 4° C. Prior to storage, initial concentrations of aceclidinewere measured using high-pass liquid chromatography (“HPLC”). The amountof aceclidine in each solution was calculated by the area under theprincipal peak compared to a reference solution of aceclidine. Sampleswere then subject to storage for 3 months. Aceclidine measurements weretaken at 1, 2 and 3 months. Results of the stability test are shown inTable 7.

TABLE 7 Stability of Aceclidine in Cold Chain Storage 25° C. 4° C.Initial 100% 100% 1 month 92% 93% 2 months 75% 92% 3 months 50% 88%

As seen in Table 7 “cold chain storage” or storage of the aceclidinecomposition at from 2° C. to 8° C. resulted in a significant increase instability of aceclidine at all 3 time points.

Example 11 Improved Distance Vision Using Separate Aceclidine andDiluent Formulations

First Container or Chamber:

aceclidine at a concentration of about 1.50% w/v lyophilized withmannitol as a cryoprecipitate at a concentration of about 2.5% w/v;

Second Container or Chamber:

tropicamide at a concentration of about 0.042% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;optionally citrate at a concentration of about 0.1% w/v;optionally BAK as a preservative at a concentration of about 0.02% w/v.6 subjects were given a Snellen Chart vision exam and their results wererecorded and reproduced in Table 8 below. These 6 subjects were thenadministered a dose of a composition immediately above. The 6 subjectwere then retested 10 minutes, 1 hour, 2 hours and 4 hours and 8 hoursafter administration.

TABLE 8 Distance Vision Improvement After After After After After Before(10 min) (1 hr) (2 hrs) (4 hrs) (8 hrs) Eye Left Right Left Right LeftRight Left Right Left Right Left Right #1 20.20 20.20 20.15 20.15 20.1520.15 20.15 20.15 20.15 20.15 20.15 20.15 #2 20.800 20.400 20.50 20.5020.50 20.50 20.50 20.50 20.50 20.50 20.50 20.50 #3 20.100 20.200 20.1520.20 20.15 20.20 20.15 20.20 20.20 20.20 20.20 20.20 #4 20.50 20.4020.15 20.15 20.15 20.15 20.15 20.15 20.15 20.15 20.15 20.15

As seen in Table 8 the administration of a composition comprisingaceclidine and tropicamide to the eye of subjects with either perfect(20.20) or less than perfect distance vision (20.>20) resulted inimprovement of distance vision. Among those with perfect distance visionthe improvement was as great as 30% (subject #1). Among those with lessthan perfect distance vision the improvement was as great as 1500%(subject #2).

Example 12 Effects of Mannitol and Carbopol® 940 on Pupil Size, DistanceVision and Near Vision

TABLE 9 Effects of Mannitol and Carbopol ® 940 A B C D E F Aceclidine1.42% 1.50% 1.50% 1.48% 1.65% 1.75% Tropicamide  0.042%  0.042%  0.042% 0.042%  0.042%  0.042%  Polyoxyl 40 5.50% 5.50% 5.50% 5.50% 5.50% 5.50%stearate Mannitol 2.50% 4.00% 4.00% 2.50% 2.50% Citrate Buffer pH 5.0Citrate only 0.10% 0.10% 0.10% 0.10% 0.10% Acetate buffer   3 mM   3 mM  3 mM   3 mM   3 mM pH 4.75 BAK* 0.01% 0.01% 0.01% 0.01% 0.01% 0.01%Carbopol ® 940 0.09% HPMC 0.30% Pupil (mm) 1.8 2.1 2.4 1.9 2 1.9 1 hr VAcc D Pre 20.20 20.20 20.20 20.20 20.20 20.20 Post 20.15+ 20.20+ 20.2020.15+ 20.15+ 20.15+ VA sc N Pre 8 pt 8 pt 8 pt 8 pt 8 pt 8 pt Post 5 pt6 pt 8 pt 5 pt 6 pt 5 pt Duration (hrs) 6.5 5.5 5.5 6.5 6 6 VA = visualacuity cc = with correction sc = without correction D = distance visionN = near vision *BAK may also be at 0.02%

Pupil size based on direct Orbscan® and Marco pupillometry video screencalibration (Orbscan is a registered trademark of Technolas PerfectVision GMBH).

As shown when comparing formulas A, B and C the addition of mannitolresulted in reduced pupil miosis and less distance and near unaidedvision improvement; but this suppression was largely neutralized byaddition of Carbopol® 940 (formula D; 0.18% and 0.50% Carbopol® 940resulted in similar effects as 0.09%, data not shown) or increasing theaceclidine concentration from about 1.40% to about 1.60%-1.75%.

Example 13 Predicted 25° C. Stable Aceclidine Formulations

Composition:

aceclidine at a concentration of about 1.48% w/v;tropicamide at a concentration of about 0.042% w/v;polyoxyl 40 stearate at a concentration of about 5.5% w/v;mannitol at a concentration of about 2.5% w/v;Carbopol® 940 (carbomer 940) at a concentration of about 0.09% w/v;optionally citrate at a concentration of about 0.2% w/v;optionally acetate or phosphate buffer at a concentration of about 3.0mM;optionally a preservative such as BAK at a concentration of about 0.02%w/v;wherein said composition has a pH of about 4.75.

Composition:

aceclidine at a concentration of about 1.48% w/v;tropicamide at a concentration of about 0.042% w/v;polyoxyl stearate at a concentration of about 4.0% w/v;mannitol at a concentration of about 4.0% w/v;Carbopol® 940 (carbomer 940) at a concentration of about 0.09% w/v;optionally citrate at a concentration of about 0.2% w/v;optionally acetate buffer at a concentration of about 3.0 mM;optionally a preservative such as BAK at a concentration of about 0.02%w/v;wherein said composition has a pH of about 4.75.

Example 14 Dual-Chamber Delivery

General Formula:

Lyophilized Composition: Aceclidine 1.55%-1.75% w/v Mannitol 2.5% w/vDiluent Composition: Tropicamide 0.042% w/v

Polyoxyl 40 stearate 5.5% w/vCarbopol® 940 0.09% to 1.0% w/v, preferably 0.5% to 0.9% w/v

BAK 0.02% w/v

Citrate, phosphate or acetate buffer at pH 4.75-5.0 3 mM-100 mM.

Formula II:

Lyophilized Composition: Aceclidine 1.65% w/v Mannitol 2.5% w/v DiluentComposition: Tropicamide 0.042% w/v

Polyoxyl 40 stearate 5.5% w/vOptionally BAK 0.02% w/v or a combination of BAK, sorbate and borateCitrate buffer at 3 mMpH of 5.0

Formula III:

Lyophilized Composition: Aceclidine 1.75% w/v Mannitol 2.5% w/v DiluentComposition: Tropicamide 0.042% w/v

Polyoxyl 40 stearate 5.5% w/vOptionally citrate 0.1% w/v

Optionally BAK 0.02% w/v

Optionally acetate, citrate, citrophosphate or phosphate buffer at 3 to10 mMpH of 4.75 to 5.5.

Method

Aceclidine can be packaged in a convenient dual chamber unit dose packallowing complete mixing prior to installation. An assembly comprisingtwo chambers of a unit-dose container are separated by an impermeablethin membrane, or thick membrane with thin central region. Aceclidine islyophilized with mannitol as a cryoprecipitate and placed within thebase of the unit dose container and sealed at its end creating alyophilized chamber (first chamber). Preferably the lyophilized chamberis vacuum sealed and/or purged of air with nitrogen gas both before andwhile being sealed. An ophthalmologically effective diluent formulationas listed above is placed at the apex of the unit dose and sealed at itsend creating a diluent chamber (second chamber). The user may thensimply pinch the diluent chamber firmly, creating a break in theimpermeable membrane between the lyophilized chamber and diluent chamberand releasing the lyophilized aceclidine into the diluent chamber withpremixing resulting in a suspension or a solubilized solution prior tosubject topical instillation.

The assembly may be optionally designed to effect an automaticcompression of the diluent chamber causing the impermeable membrane torupture and deliver the drug into the diluent chamber. An example ofsuch an automatic compression may occur by placing the unit dose packsin a rack assembly where an upper plastic planar assembly is designedwith a smaller opening than the diameter of the unit dose pack at itsapex (i.e. the diluent chamber), wherein pulling a tab of the unit dosemay then squeeze the upper chamber and effect its internal rupture andmixing of the lyophilized tyrosine kinase inhibitor andophthalmologically effective diluent. Alternatively, the puncturing ofthe impermeable membrane is effected by the turning of a screw cap thusmixing the lyophilized aceclidine with the preferred diluent.

Example 15 Use of Preferred Embodiment for Dual-Chamber Delivery

Formula

Vial A: Lyophylized Powder

1.65% w/v aceclidine2.5% w/v mannitol

Vial B: Diluent

0.042% w/v tropicamide5.5% w/v polyoxyl 40 stearate0.01% w/v BAK or a combination of BAK, sorbate and borate3 mM citrate bufferpH 5.0

Method

One cubic centimeter (“cc”) of diluent from Vial B was injected intoVial A and the lyophilized powder was allowed to completely solubilizeover several minutes. Two drops were then administered to each eye via a3 cc syringe with the needle removed. Acuity measurements were thentaken in a room whose sole illumination was produced by the backlitvisual acuity charting, where pupil measurement was taken 3 meters backwith fellow eye viewing the illuminated chart. A Neuroptix pupillometerwas used for all pupil readings. A neutral density filter of 3 cd/m wasplaced over the illumination chart for dim illumination low contrastacuity testing. Distance vision was tested at 3 meters (m) using a chartdesigned for that distance. Near vision was tested at 40 cm, 66 cm, and100 cm binocularly.

TABLE 10 Visual Acuity after Topical Instillation of Dual-ChamberAceclidine Composition LogMAR Test OD OS OU Baseline Pupil Size (mm)4.20 4.3 — 15 min after instillation 1.90 1.9 — 30 min afterinstillation 2.10 —* — Baseline Distance (3 m) 0.14 0 — 0.25 h Distance(3 m) −0.08 −0.1 — 0.5 h Distance (3 m) −0.1 0 — 1 h Distance (3 m)−0.18 −0.1 — Baseline Low-luminance 0.3 0.14 — 0.25 h Low-luminance 0.080.08 — 0.5 h Low-luminance 0.12 0.08 — 1 h Low-luminance 0.02 0.08 —Baseline 40 cm 0.46 0.18 0.2 0.25 h 40 cm — — 0.12 0.5 h 40 cm — — 0.021 h 40 cm — — 0 Baseline 66 cm 0.08 0.04 −0.02 0.25 h 66 cm — — −0.120.5 h 66 cm — — −0.14 1 h 66 cm — — −0.12 Baseline 100 cm 0.06 0.02−0.08 0.25 h 100 cm — — −0.14 0.5 h 100 cm — — −0.18 1 h 100 cm — — −0.2Abbreviations: m indicates meters, mm indicates millimeters, cmindicates centimeters, h indicates hour, OD indicates right eye; OSindicates left eye and OU indicates both eyes. LogMAR is a visual acuitychart specialized for research settings. LogMAR values approximate toSnellen Chart values as follows: 1.00 (20/200), 0.90 (20.160), 0.80(20.125), 0.70 (20.100), 0.60 (20.80), 0.50, (20.63), 0.40 (20.50), 0.30(20.40), 0.20 (20.32), 0.10 (20.25), 0.00 (20.20), −0.10 (20.16), −0.20(20.13), −0.30 (20.10). *indicates failure of the Neuroptixpupillometer. Results

As indicated in Table 10 instillation of the dual-chamber aceclidinecomposition resulted in improved distance vision, near vision andlow-light vision. Specifically, distance vision gradually improved from0.14 (about 20.28) in the left eye to −0.18 (about 20.13) and from 0.00(20.20) in the right eye to −0.1 (20.16). Distance vision in low lightimproved from 0.3 (20.40) in the left eye to 0.02 (about 20.21) and from0.14 (about 20.28) in the right eye to 0.08 (about 20.24). Near visionat 40 cm (16 inches) improved from about 0.2 (20.32) to 0 (20.20). Nearvision at 66 cm (26 inches) improved from about −0.02 (about 20.19) to−0.12 (about 20.15). Near vision at 100 cm (39 inches) improved fromabout −0.08 (about 20/17) to −0.2 (20.13).

Example 16 Correction of Presbyopia with No Reduction of Distance Vision

Formulation:

pilocarpine at a concentration of about 1.25% w/vtropicamide at a concentration of about 0.035% w/vpolyoxyl 40 stearate at a concentration of about 5.5% w/vcarbomer 940 at a concentration of about 0.50% w/vcitric acid monohydrate at a concentration of about 0.10% w/vacetate buffer at a concentration of about 3.0 millimolarpH of about 5.

1 drop of the above formulation was instilled into the right eye of thepatient. Prior to instillation, the patient had a near vision acuity of20.60 and a distance vision acuity of 20.20 with distance visioncorrective lenses. After instillation of the above formulation, thepatient had a near vision acuity of 20.30 and a distance vision acuityof 20.20. The corrected near vision was not accompanied by any ciliaryspasm and had a redness of about 0.5. Post-instillation pupil size wasestimated to be about 2.0 to 2.2 millimeters. Compared to prior artpilocarpine use, the above formulation surprisingly and unexpectedlyresulted in no reduction in distance vision and was not accompanied byside effects such as ciliary spasm.

Example 17 The Effect of Myopic Spherical Equivalent Fraction onDistance Vision Acuity at Various Pupil Sizes Method

A subject with a best corrected 20.15 acuity eye was subject torefractive correction from 0.0 diopters (“D”) to the myopic targetsindicated (−0.5 D to −6 D). At all diopters tested the subject wastopically administered a combination of aceclidine and tropicamide toadjust pupil size.

Results

At a pupil size above 2.5 mm only modest pinhole optical correction ofdistance vision was seen, and at 3.0 mm or above essentially nocorrection was seen. See FIG. 2. At a pupil size below 2.0 mm there ismodest continued improvement in distance vision, but below 1.60 mmdimming becomes considerable and distance acuity was not measured.Importantly, at or above −1 D, 1 line of vision is lost, whereas at 0.50D vision loss is barely detectable. The implications of this are, thoughnot wishing to be held to particular theory, important considerations ofthe present invention:

-   -   a. as a general observation, pinhole optics substantially        correct refractive error at or about 2.0 mm or less;    -   b. the improvement is degraded by about 1 line of vision or more        once additional or induced miosis of 1.0 D or more occurs;    -   c. 0.50 D of induced myopia has little effect on distance vision        for a 1.7-2.0 mm pupil;    -   d. the present invention demonstrates that pupil sizes ranging        from about 1.7-2.1 mm result in substantial near vision        improvement with no demonstrable accommodation;    -   e. the ability to dissociate ciliary contraction from pupillary        miosis sufficient to create a 1.7-2.1 mm pupil range, with        induction of about, but no greater than, 0.50 D of accommodation        results in excellent distance vision, pinhole optic enhanced        near vision, and additive accommodative near vision improvement;        and    -   f. because the presbyopic range for ages 45 to 55 for example is        +1.00 to +1.50 for emmetropes, the additive benefit of 0.50 D of        accommodative tone might further enhance near vision improvement        without deleterious effect on distance.

Example 18 Effect of Pilocarpine and Tropicamide Formulas on Near andDistance Vision and Pupil Size

Formulas

Formula #34: Pilocarpine 1.00% w/v Tropicamide 0.042% w/v

Polyoxyl 40 stearate 5.5% w/v

Citric Acid 0.10% w/v Carbopol 0.85% w/v

Acetate buffer 3 mMpH 5.0

Formula #35: Pilocarpine 1.50% w/v Tropicamide 0.035% w/v

Polyoxyl 40 stearate 5.5% w/v

Citric Acid 0.10% w/v Carbopol 0.85% w/v

Acetate buffer 3 mMpH 5.0

Method

Formula #34 and Formula #35 were each instilled at separate times in theeye of a subject, which had 20.20 distance vision acuity and 20.40 nearvision acuity and a pupil size of 5 millimeters. Distance and nearvision were checked using Jaeger near charts and Snellen distance acuitycharts at the times indicated in Table 11. Pupil size was measured usingan Orbscan® Hz with no room illumination or adjustment for measuredpupil size and compared with a Marco video caliper adjusted scale.

Results

Formula #34 constricted the pupil to 3.5 mm at 1 hour with a peak of 3mm at 4 hours post instillation. Instillation of Formula #34 had noeffect on either near or distance vision. Not wishing to be held toparticular theory, this is believed to be due to insufficient pupillaryconstriction for enhanced depth of focus. Slight pupil miosis occurred40 minutes after instillation and resulted in only slight ciliarysensation and redness and no discomfort beyond a medium discomfort for15 seconds following instillation. See Table 11.

Formula #35 constricted the pupil to 1.9 mm after 1 hour and maintainedconstriction to 2 mm and 2.1 mm at 4 and 6 hours, respectively.Instillation of Formula #35 resulted in improvement of distance visionto 20.15 for 5 hours, which returned to 20.20 at 7 hours. Further,instillation of Formula #35 resulted in improvement of near vision to20.20 at 4 hours, 20.25 at 7 hours and 20.30 at 8 hours postinstillation. Pupil miosis occurred 20 minutes after instillation andresulted in only slight ciliary sensation and redness and no discomfortbeyond a medium discomfort for 15 seconds following instillation. SeeTable 11.

TABLE 11 Effect of Pilocarpine and Tropicamide Formula on Vision andPupil Size Formula #34 #35 DBVCA baseline 20.20 20.20 DBVCA 1 hour *20.20 20.15 DBVCA 2 hours * 20.20 20.15 DBVCA 3 hours * 20.20 20.15DBVCA 4 hours * 20.20 20.15 DBVCA 5 hours * 20.20 20.15 DBVCA 7 hours *20.20 20.20 DCNVA baseline 20.40 (J4) 20.40 (J4) DCNVA 1 hour * NoChange 20.20 (J1) DCNVA 2 hours * No Change 20.20 (J1) DCNVA 3 hours *No Change 20.20 (J1) DCNVA 4 hours * No Change 20.20 (J1) DCNVA 5hours * No Change 20.25 (J2) DCNVA 7 hours No Change 20.25 (J2) DCNVA 8hours No Change 20.30 (J3) Pupil (mm) baseline 5 5 Pupil 1 hour 3.5 1.9Pupil 4 hours 3 2 Pupil 6 hours 2.1 Onset (min) 40 20 Duration (decaypoint, hrs) 0 7, 8 Ciliary Sensation (BA) 0.5 0.5 Redness (R) 0.5 0.5Comfort (C) 4 4 Other Sting 2.5 + for Sting 2.5 + for 15 sec 15 sec BA =ciliary sensation: 0.5 slight sharp well tolerated sensation, 1.0discomfort, 2.0-4.0 definite pain to intolerable R = redness 0-4 scale,where 1 = trace, 2 = moderate, 3 = severe, 4 = chemosis (swelling andredness) C = comfort 0-4 scale where 4 = max totally comfortable; whereinitial drop effect 1^(st) seconds measured as other.

Formula #35 is an improvement over the use of a formula containing 1%pilocarpine and 0.12% oxymetazoline as described in U.S. PatentApplication Publication No. 2014/0113946 (“Allergan Formula”).Specifically, the Allergan Formula resulted in near vision correction of3.5 lines up to 4 hours after instillation and 2.1 lines of correctionat 6 hours post instillation. Instillation of Formula #35 resulted incomparable, yet longer lasting, near vision correction with 3 lines ofcorrection up to 4 hours after instillation and 2 lines of correction atmore than 7 hours post instillation.

Further, instillation of Formula #35 resulted in an unexpected andmarked improvement in distance vision over the Allergan Formula.Specifically, instillation of the Allergan Formula resulted in adeterioration in distance vision of −0.65 lines (26% reduction) for upto 4 hours; whereas instillation of Formula #35 resulted in animprovement of distance vision of 0.7 lines (26% increase) for more than5 hours.

Example 19 Effect of Another Pilocarpine and Tropicamide Formula on Nearand Distance Vision and Pupil Size

Formula

Formula #36: Pilocarpine 1.25% w/v Tropicamide 0.035% w/v

Polyoxyl 40 stearate 5.5% w/v

Citric Acid 0.10% w/v Carbopol 0.85% w/v

Acetate buffer 3 mMpH 5.0

Method

Formula #36 was applied under the same experimental conditions as inExample 18.

Results

Instillation of Formula #36 resulted in improvement of distance visionto 20.15 for 2 hours. Further, instillation of Formula #36 resulted inan onset of about 30 minutes for near vision enhancement with a maximumimprovement to about J2 at 1 hour (20.25 near). After about four hoursthe enhanced distance and near vision effects rapidly diminished.

What is claimed is:
 1. An ophthalmological composition for the treatmentof presbyopia comprising a muscarinic agonist and a cycloplegic agent.2. The composition of claim 1 wherein the muscarinic agonist is selectedfrom the group consisting of pilocarpine, aceclidine, talsaclidine,sabcomeline, cevimeline, WAY-132983, AFB267B (NGX267), AC-42, AC-260584,77-LH-28-1, and LY593039 or a pharmaceutically acceptable salt, ester,analogue, prodrug or derivative thereof.
 3. The composition of claim 1wherein the cycloplegic agent is selected from the group consisting ofpirenzepine, tropicamide, cyclopentolate hydrochloride,4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), AF-DX 384,methoctramine, tripitramine, darifenacin, solifenacin, tolterodine,oxybutynin, ipratropium, oxitropium, tiotropium, otenzepad and acombination thereof.
 4. The composition of claim 1 wherein the ratio ofmuscarinic agonist to cycloplegic agent is greater than about 25:1. 5.The composition of claim 4 wherein the ratio of muscarinic agonist tocycloplegic agent is greater than about 40:1.
 6. A method of treatingpresbyopia comprising administering a therapeutically effective amountof a composition of claim 1 to a patient in need thereof.
 7. The methodof claim 6 wherein distance vision acuity of the patient is not reduced.8. An ophthalmological composition for the treatment of presbyopiacomprising pilocarpine or a pharmaceutically acceptable salt, ester,analogue, prodrug or derivative thereof and a cycloplegic agent.
 9. Thecomposition of claim 8 wherein the cycloplegic agent is selected fromthe group consisting of pirenzepine, tropicamide, cyclopentolatehydrochloride, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP),AF-DX 384, methoctramine, tripitramine, darifenacin, solifenacin,tolterodine, oxybutynin, ipratropium, oxitropium, tiotropium, otenzepadand a combination thereof.
 10. The composition of claim 8 whereinpilocarpine is at a concentration from about 0.5% to about 2.5% w/v andthe cycloplegic agent is at a concentration from about 0.010% to about0.1% w/v, wherein w/v denotes weight by volume.
 11. The composition ofclaim 10 wherein pilocarpine is at a concentration of about 1.5% w/v.12. A method of treating presbyopia comprising administering atherapeutically effective amount of a composition of claim 8 to apatient in need thereof.
 13. The method of claim 12 wherein distancevision acuity of the patient is not reduced.
 14. An ophthalmologicalcomposition for the treatment of presbyopia comprising pilocarpine andtropicamide.
 15. The composition of claim 14 wherein pilocarpine, or anypharmaceutically acceptable salts, esters, analogues, prodrugs orderivatives thereof, is at a concentration from about 0.5% to about 2.5%w/v and tropicamide is at a concentration from about 0.010% to about0.1% w/v, wherein w/v denotes weight by volume.
 16. The composition ofclaim 15 wherein pilocarpine is at a concentration of about 1.5% w/v andtropicamide is at a concentration of about 0.035% w/v.
 17. Thecomposition of claim 15 wherein pilocarpine is at a concentration ofabout 0.95% w/v and tropicamide is at a concentration of about 0.015%w/v.
 18. A method of treating presbyopia comprising administering atherapeutically effective amount of a composition of claim 14 to apatient in need thereof.
 19. The method of claim 18 wherein distancevision acuity of the patient is not reduced.